Non-alcoholic fatty liver disease (NAFLD) was
proposed by Ludwig in 1986. It refers to a fatty liver disease
characterized by excessive fat deposition in hepatocytes (with a
fat content of ≥5%), excluding alcohol and other factors related to
chronic liver diseases (1-4).
In 2020, the Asian Pacific Association for the Study of the Liver
proposed the term 'metabolic dysfunction-associated fatty liver
disease (MAFLD)', emphasizing the role of metabolic disorders in
the progression of fatty liver disease (5). In 2023, an international panel of
experts reached a consensus and the European Association for the
Study of the Liver, from an etiological perspective, renamed it as
'metabolic dysfunction-associated steatotic liver disease (MASLD)'
(6,7). This change highlights the critical
role of metabolic abnormalities in the occurrence and development
of the disease (8). While
avoiding 'stigmatization', this concept also provides explanations
for the coexistence of MASLD and alcoholic-associated liver disease
(9,10).
The etiology of MASLD is complex, with its core
being the interplay between metabolic dysfunction (such as insulin
resistance and dyslipidemia) and multifactorial elements (including
genetics, environment and lifestyle), rather than being attributed
to a single factor. Researchers have established various animal
models of MASLD using diverse methodologies to investigate its
pathophysiological characteristics. Currently, common
interventional drugs mainly include: Farnesoid X receptor agonists,
peroxisome proliferator-activated receptor (PPAR)α/γ/δ agonists,
GLP-1 agonists and fibroblast growth factor 19/21 analogs (11). For individuals with a body mass
index >35, bariatric surgery is primarily recommended. In the
treatment of MASLD, although chemical drugs have advanced rapidly,
their efficacy remains limited with notable adverse effects. By
contrast, traditional Chinese medicine (TCM) not only enables
comprehensive regulation targeting the multifactorial pathogenesis
of MASLD, but also strives to improve the quality of life of
patients, thereby opening up new possibilities for the management
of MASLD (12).
In recent years, influenced by unhealthy lifestyles
and dietary habits, the prevalence of MASLD has been increasing
annually. The global incidence rate has reached 25-35%, with a
prevalence of 29.2% in China (13). It is projected that the number of
MASLD patients in China will reach 315 million by 2030, imposing a
heavy economic burden on society (14). Even mild fatty liver disease
increases the risk of death by 71% and this risk is positively
associated with the severity of the disease (14). Currently, while the incidence of
viral liver diseases is on the decline, the incidence of MASLD is
rising, making early intervention for MASLD an urgent priority. The
present study analyzed the pathogenesis, experimental models and
therapeutic approaches of MASLD, aiming to provide novel scientific
insights and strategies for future research, clinical treatment and
drug development.
To compile the research progress on the
pathogenesis, model and treatment of MASLD as comprehensively as
possible, the present study searched for 'pathogenesis', 'model',
'treatment' and 'traditional Chinese medicine' in existing
scientific databases. The references related to MASLD were obtained
from both online and offline databases, spanning the period from
1980-2025 with a total of 385 references. Online databases included
PubMed (https://pubmed.ncbi.nlm.nih.gov/), Web of Science
(https://www.webofscience.com/), Elsevier
(https://www.elsever.com/), Sci-Hub (https://sci-hub.st/), Wiley (https://www.wiley.com/), SpringerLink (https://link.springer.com/), Google Scholar
(https://scholar.google.com/), EMBASE
(https://www.embase.com/), Cochrane Library and
China National Knowledge Infrastructure (CNKI) (https://www.cnki.net/). Other references were obtained
from ancient Chinese books, pharmacopoeias and other articles. The
present authors used BioGDP (https://biogdp.com/) as well as Adobe Illustrator
(Adobe Systems, Inc.) for graphing.
The pathogenesis of MASLD remains unclear due to its
complexity and diversity. As the main metabolic organ, the liver's
metabolism is closely connected with multiple organs and systems in
the human body. There are intricate links between these organs and
systems. Some consider that the hypothesis of 'multiple parallel
strikes' could be an improved explanation of the causes of MASLD
development and these strikes included oxidative stress,
endoplasmic reticulum (ER) stress, lipid metabolism disorders,
abnormal adipokines and cytokines production and mitochondrial
dysfunction (15). One study
found that mitochondrial dysfunction might be a central factor in
the development of MASLD and other factors that cause disease
progression also involve mitochondrial dysfunction (16). The pathogenesis of MASLD is now
being investigated by combining different pathogenic pathways for
an improved understanding of metabolic diseases.
The 'first strike' mainly refers to insulin
resistance (IR) caused by obesity and type 2 diabetes mellitus
(T2DM) and hepatic steatosis caused by excessive accumulation of
triglyceride (TG) and cholesterol in the liver parenchymal cells in
the form of lipid droplets. The 'Two-hit' hypothesis includes
inflammatory cytokines, lipid peroxidation, mitochondrial
dysfunction and oxidative stress (17), of which oxidative stress is the
primary driver (18). This
hypothesis posits that with steatosis, the liver undergoes ER
stress, oxidative stress and mitochondrial dysfunction, leading to
an increase in oxidative metabolites, hepatocellular damage and
secretion of a large number of inflammatory factors, which
ultimately leads to further deterioration into liver disease, liver
fibrosis, cirrhosis, inflammatory necrosis and other reactions
(19,20). In the early stages of MASLD,
classical activation of macrophage M1 in the liver can promote
further inflammation and IR, as well as steatosis (21). Among them, inflammatory cytokines
such as interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α),
IL-1β and cyclooxygenase-2 contribute to the development of chronic
inflammatory diseases (22).
IL-6 has been shown to have both anti-inflammatory and
pro-inflammatory effects, but its role in MASLD is controversial.
IL-10, produced primarily by monocytes and B cells, is an
anti-inflammatory factor with immunomodulatory properties (22). Other inflammatory cells of the
innate immune system, such as natural killer T cell and natural
killer cells, also play the important roles in the pathogenesis of
MASLD and MASH (21). However,
the factors that induce MASLD in clinical practice are diverse and
as research has deepened, the two-hit hypothesis has already shown
certain limitations and cannot fully explain the pathogenesis of
MASLD. Recently, the 'three-strike' and 'multiple-strike'
hypotheses have been proposed, which include gut microbiota toxins,
IR, cytokines and inflammation, oxidative stress due to
mitochondrial dysfunction, lipid peroxidation, ER stress, intrinsic
immune regulation, circadian rhythm disruption and immune system
development. Imbalances, circadian patterns and genetics are all
parallel and mutually reinforcing factors that contribute to the
onset and development of MASLD (23,24) (Fig. 1).
The role of liver sinusoidal endothelial cell (LSEC)
in the development and progression of MASLD is being gradually
recognized. LSEC is the most predominant liver nonparenchymal cell
(NPC), accounting for 15-20% of the total number of hepatocytes but
only 3% of the total volume of the liver (25). The biggest difference between
LSECs and other vascular endothelial cells is the presence of
window pores and the lack of a basement membrane. LSECs are
considered the most permeable endothelial cells in mammals
(25). Window pores are small
pores with diameters ranging from 50-200 nm, accounting for 2-20%
of the endothelial surface area (26). MASLD manifests as NAFL in the
early stage, which is not accompanied, or only accompanied by mild,
inflammation. LSEC acts as the first line of defense in the
initiation of MASLD (27),
exerting anti-inflammatory effects, preventing the over-activation
of the hepatic immune system and maintaining the microenvironmental
homeostasis of hepatic sinusoids. It has been shown that the unique
window pore structure of LSECs in a physiological state serves an
important role in maintaining the stability of the liver, which
manifests pro-vasodilatory, strong endocytosis, anti-inflammatory
and anti-fibrotic effects (28).
This window pore regulates the act in the endothelial cell skeleton
of LSECs through the form of calcium-calmodulin-actin complex to
adjust and control the size of the window pore on the endothelial
cells of LSEC; if the size, number, and permeability of window
pores in LSECs could not be effectively improved, they would
disappear in the course of time. From the initial manifestation of
fat accumulation to inflammatory symptoms, as well as hepatic
fibrosis and in severe cases, cirrhosis, LSEC regulates blood flow
through the secretion of two substances, nitric oxide (NO) and
endothelin-1 (ET-1) (27). NO
promotes vasodilatation and ET-1 induces vasoconstriction. Reduced
NO bioavailability induces LSEC capillarization characterized by
loss of the LSEC window pore and basement membrane formation and
leads to an imbalance in its secretion of vasoactive substances,
which contributes to MASLD progression. With the progression of
MASLD, LSEC undergoes capillarization and hepatic sinusoidal
endothelial dysfunction, which gradually shifts from an
anti-inflammatory to a pro-inflammatory phenotype and promotes the
progression of inflammation, fibrosis and angiogenesis. Hepatic
sinusoidal endothelial dysfunction precedes the development of
hepatic inflammation or fibrosis. It is a major feature and early
event in MASLD pathogenesis (29).
IR refers to the phenomenon of reduced sensitivity
of tissues and organs to insulin, which is the initiation and
central link in the progression of MASLD (30). It has been found that the degree
of IR in MASLD patients is positively associated with the severity
of the disease (31). IR acts on
target organs mainly the liver, skeletal muscle and adipose tissue;
the body's sensitivity to insulin is reduced, so that the
biological effect of insulin on target organs is reduced and
glucose uptake and utilization are reduced, thus failing to
maintain blood glucose stability. Compensatory overproduction of
pancreatic islets and eventual development of hyperinsulinemia,
result in elevated hepatic synthesis and accumulation of total
cholesterol (TC) and elevated low-density lipoprotein (LDL) levels,
leading to inactivation of the enzyme LDL lipase, which is critical
for cholesterol clearance. Large amounts of TG cannot be cleared
and IR-induced hyperinsulinemia inhibits apolipoprotein B100
synthesis and reduces very low-density lipoprotein (VLDL) related
lipid output from hepatocytes (32). In addition, IR leads to
decreasing lipid metabolism, increasing lipolysis and hepatic
uptake of large amounts of free fatty acid (FFA). By contrast,
fatty acid β-oxidation is inhibited by hyperinsulinemia and large
amounts of FFA are deposited in the liver, exacerbating
hepatocellular steatosis (33).
Excessive deposition of lipids further exacerbates IR and they are
mutually influencing and reinforcing processes (34). MASLD also leads to lower levels
of adiponectin (ADPN), a protein released from adipocytes. ADPN
aggravates steatosis in hepatocytes (35) and plays a role in regulating
glucose and lipid metabolism, as well as exhibiting
anti-inflammatory and anti-insulin resistance effects (36). In addition, Shah and Fonseca
(37) found that iron overload
could reduce insulin sensitivity and IR, which are closely related
to the occurrence of MASLD. The main reason is that iron can
activate the nuclear factor-kappa B (NF-κB) signaling pathway.
Activation of this pathway causes hepatocytes to produce an
inflammatory response, which accelerates the formation of MASLD.
Although iron is an essential trace element in the human body, a
study found that iron overload is closely related to the occurrence
of MASLD (37). Iron overload
can generate reactive oxygen species (ROS) and cause oxidative
stress. Iron overload can also affect lipid metabolism and insulin
signaling, which can accelerate the progression of MASLD (38). Using hepatic puncture biopsy,
Nelson et al (39)
discovered that 34.5% of 849 patients with MASLD had intrahepatic
iron deposition, which suggested that iron deposition was a risk
factor for the progression of MASLD patients to advanced liver
diseases.
Adipokines are small-molecule proteins secreted by
tissues to regulate adipocytes, mainly including leptin (LP) and
ADPN. A study (40) found that
IR is closely related to the secretion of LP, resistin and ADPN.
ADPN is an adipokine that affects hepatic fat and glucose
metabolism, which interacts with adiponectin receptor1 and
adiponectin receptor 2. Adiponectin receptor 2 is mainly expressed
in liver tissues. Clinical studies have shown that the serum level
of ADPN in patients with MASLD is low and negatively is associated
with the severity of fatty liver (40). In addition, serum lipocalin
levels are reduced in MASLD patients and are associated with the
degree of hepatic necroinflammation, leading to the suggestion that
hypo-lipocalinemia will lead to the progression of MASLD, which may
be related to the fact that ADPN acts on the sterol regulatory
element-binding protein-1C to inhibit lipolysis of fats (41). Studies have shown a close
relationship between LP and the development of MASLD and that LP
can lead to the activation of hepatic LP and can lead to the
activation of hepatic stellate cells in MASLD and promote the
development of MASLD to liver fibrosis (41). Moreover, LP is also associated
with IR; when the feedback regulation mechanism between pancreatic
islets-adipocytes is damaged, the sensitivity of insulin to LP
decreases. It makes the fatty acid content of hepatocytes rise,
which promotes the increase in the synthesis of TGs in the
hepatocytes, leading to the formation of MASLD (42). Wang et al (43) found that the amount of ADPN
expression can be used to predict the occurrence of MASLD to a
certain extent. Resistin is a prepeptide adipocytokine containing a
108-amino-acid segment, named after its anti-insulin effect. In
another study, RES was found to be highly expressed in adipose
tissue and serum of both high-fat diet-induced obese rats and
transgenic obese rats (44).
Activation of resistin can induce the release of inflammatory
factors and promote the development of liver fibrosis (45).
Lipotoxicity refers to lipid metabolism disorders
leading to an increase in FFA, excessive FFA makes pancreatic islet
β-cells dysfunctional, inducing them to produce a large amount of
NO, causing a series of cytotoxic injuries. Markedly increased
plasma FFA level in MASLD patients is the main reason for increased
IR in the body. In addition, increasing plasma FFA content leads to
fatty acid oxidation overload in hepatocytes, induces mitochondrial
damage and generates large amounts of ROS, causing oxidative
stress, ER stress and inflammatory response, which advances the
process of disease progression. The mechanisms of hepatic fatty
acid metabolism on MASLD are shown in Fig. 2.
The normal number of hepatocytes is controlled by
hepatocyte apoptosis, which maintains the liver at a normal size
and plays an important role in the development of the liver and the
maintenance of internal homeostasis, it is the defender of
hepatocytes against infections, tumors and autoimmune reactions;
under pathological conditions apoptosis of hepatocytes is the
central link in the basis of injury and other liver diseases.
Lipotoxicity induces apoptosis in hepatocytes, called
lipoapoptosis. It has been demonstrated that FFA-treated
hepatocytes show an increase in the expression of pro-apoptotic
proteins and apoptosis regulators upregulated by tumor suppressor
genes, a process that is accompanied by a decrease in the
expression of the anti-apoptotic protein B-cell lymphoma-2. The
aforementioned process initiates the mitochondria-induced apoptosis
pathway, which activates caspase-3,6,7 leading to apoptosis
(46). Hepatocyte apoptosis is
closely related to the pathogenesis of MASLD (47).
Mitochondria are an important site for hepatic FFA
oxidation. When FFA and related metabolites in the liver increase
in excess, it causes mitochondrial microstructure swelling and
mitochondrial dysfunction, resulting in impaired β-oxidation,
altering the permeability of the ER membrane, inducing the
production of a large number of ROS. ATP generation is reduced,
causing oxidative stress and mitochondrial damage (48). In the meantime, ROS generated by
oxidative stress in the mitochondrial membrane react with
unsaturated fatty acids of mitochondrial membrane phospholipids,
nucleic acids and other macromolecules to cause lipid peroxidation
and the products of lipid peroxidation produce endogenous ROS and
O2−, which can damage mitochondrial DNA structure and
further diminish the anti-oxidant effect of mitochondria (49). In addition, ROS generated by
oxidative stress in hepatocytes can trigger an inflammatory
response. This response induces neutrophil infiltration and
activates Kupffer cells (KCs) to secrete ROS and TNF-α. These
events create a vicious cycle of oxidative stress, leading to VLDL
deposition in the liver and the development of MASLD. Further
hepatocyte necrosis may occur due to other cytokines, such as
transforming growth factor-β (TGF-β), IL-6 and C-reactive protein
(49,50).
Persistent inflammation is the main driver of MASLD
progression to MASH and fibrosis and activation of toll-like
receptors (TLRs) is thought to be a key factor in triggering
hepatic steatotic inflammation. The liver, as a central immune
organ, possesses the largest number of resident macrophages, known
as KCs. KCs account for 35% of the liver's NPC and 80-90% of all
tissue macrophages in the body. KCs are considered to be the first
immune cells to come into contact with intestinal or hepatic
autoimmune reactive substances and are rich in the expression of
TLRs (51). Accumulation of
lipids in hepatocytes will result in lipotoxicity, which will lead
to hepatocyte damage or death. Damaged or dead hepatocytes release
damage-associated pattern molecules, including mitochondrial DNA
(mtDNA) and high mobility group protein-1 (HMGB1) (52). Among them, mtDNA can directly
activate recombinant TLR9 in KCs, triggering an inflammatory
cascade (53). Recombinant
toll-like receptor 4 (TLR4) (Fig.
3) is another TLR family member upregulated in MASLD and
lipopolysaccharide (LPS), ROS, HMGB1 and various damage-associated
molecular patterns can bind to TLR4 in KCs to promote TNF-α, IL-1β,
IL-6 and interferon-γ (IFN-γ) production of various
pro-inflammatory cytokines, thereby contributing to hepatic
inflammation and the progression of MASLD (54). In addition to triggering the
inflammatory response through lipotoxicity that causes hepatocyte
injury or death, excess FFA in the liver can also exacerbate the
inflammatory response through direct or indirect activation of
TLR4. Circulating FFA, especially saturated fatty acid (SFA), acts
as non-microbial TLR4 agonists and triggers inflammatory responses.
SFA is thought to have a similar recognition pathway to LPS, a
natural ligand of TLR4, in order to activate the TLR4 signaling
pathway, thereby triggering downstream inflammatory pathways
(55). Furthermore, to activate
TLR4, SFA is also thought to activate recombinant TLR2 to promote
the development of inflammatory responses (56). It has been shown that SFA can
activate TLR by interacting with TLR co-receptors, such as cluster
of differentiation36 (CD36) or LDL receptors, to promote
inflammation (57). In addition,
FFA can interact with various other cytokines, such as hepatocyte
nuclear factor 4-α (HNF-4α), leading to overall changes in
signaling pathways that regulate metabolism and stress (58). Lipotoxicity can also further
induce ER stress, impair autophagy and promote aseptic inflammatory
responses, thereby exacerbating hepatocyte injury and death
(59,60). Cholesterol synthesis is markedly
increased in patients with MASLD, suggesting that cholesterol may
also be one of the important driving forces in its development
(61). Cholesterol not only
promotes de novo lipid synthesis but also induces lipid
peroxidation (62). Moreover, it
has been found that increased dietary cholesterol intake leads to
hepatic inflammation and oxidative stress in mice, suggesting that
cholesterol probably plays a contributory role in the disease
progression of MASLD (63).
Lipid accumulation in hepatocytes can affect
mitochondrial function, ER membrane fluidity and calcium ion
homeostasis. It has been found that thioesterase superfamily member
2 (THEM2) promotes the uptake of saturated fatty acids by ER
phospholipid membranes, reduces ER membrane fluidity and affects
the activity of ER Ca2+associated ATPase. The
dysregulation of Ca2+ signaling can cause protein
misfolding and secretion (64).
Non-esterified fatty acids can expand the membrane structure of the
endoplasmic reticulum-mitochondria association. Changes in the
membrane structure of the ER allow Ca2+ to flow into the
cytoplasm or mitochondria, which in turn alters the open channels
of the mitochondria and cytochrome c is released into the
cytoplasm. Ca2+ entering the cytoplasm can activate the
Ca2+ dependent protein kinase, which together with
cytochrome c induces the onset of apoptosis (65). ROS generated by mitochondria can
enter the ER and trigger the unfolded protein response (UPR), which
can activate three types of ER transmembrane protein receptors:
Protein kinase RNA-like endoplasmic reticulum kinase (PERK),
activating transcription factor-6α (ATF-6α) and inosital-requiring
enzyme-1α (IRE1α), which mediate three signaling pathways. The
three transmembrane proteins mediate three signaling pathways,
which can maintain the stability of ER protein synthesis to a
certain extent in the early stage of steatosis, but under the
continuous stimulation of lipids and ROS, the three transmembrane
proteins mediate the signaling pathways that can activate cellular
inflammation and apoptosis, accelerating the progression of hepatic
steatosis (66).
In the process of hepatocellular steatosis, one of
the hallmarks of MASLD is the appearance of the UPR in hepatocytes,
which can inhibit mitochondrial lipid oxidation through the
UPR-induced ATF-6α pathway and promote fatty acid synthesis via the
PERK, ATF-6α and IRE1α signaling pathways, which together promote
intracellular lipid accumulation (67,68). Hepatocyte lipid accumulation and
ER stress form a positive feedback loop that continuously
exacerbates hepatocyte steatosis. The occurrence of chronic
inflammation in hepatocytes is also one of the main features of
metabolic disorders. The inflammatory response can activate the UPR
through three major signaling pathways (PERK, ATF-6α and IRE1α).
The UPR can also interact with NF-κB and N-terminal
kinase/activator protein 1-regulated pro-inflammatory pathways to
accelerate disease progression (66,69).
The intestinal flora is a symbiotic group of
microorganisms that act synergistically with the host. Under normal
circumstances, the intestinal flora of the human body is in a state
of equilibrium. Imbalances in the intestinal flora can be caused by
environmental factors, immune levels, bile secretion, changes in
gastric acidity and alkalinity and impaired intestinal peristalsis.
In recent years, it has been found that dysbiosis is one of the
causative factors of MASLD (70). The intestinal flora mainly
influences the liver through the 'gut-liver axis'. Normally, there
is a balance between the barrier function of the intestine and the
detoxification capacity of the liver and trace amounts of
intestinal bacteria cross the mucosa and enter the venous
bloodstream and are cleared by the liver (71). When intestinal flora dysbiosis
occurs, metabolic disorders will occur, the permeability of the
intestinal tract will increase and a large amount of intestinal
bacterial metabolites, bacterial components and other harmful
substances will enter the liver through the portal vein via the
intestinal-hepatic axis and through the enterohepatic circulation
reach the liver and bind to the TLR4 of hepatocytes and exacerbate
the hepatic inflammatory response, oxidative stress and lipid
accumulation, which further stimulate the inflammatory response.
Intestinal microorganisms change their phenotype and virulence by
sensing the various adverse signals generated during intestinal
stress, shifting from a commensal to a pathogenic mode and causing
damage to the organism (72).
Ley et al (73) found
that changes in the composition of the gut microbial community
associated with obesity as well as IR were observed after the
adoption of two different dietary patterns. IR, an important
feature of MASLD, can be improved after antibiotic treatment
(74). A study conducted by Le
et al (75) demonstrated
that when gut microbes from successfully modeled MASLD mice were
transplanted into normal control mice, the normal control mice
developed MASLD and this study strongly confirmed that the
development of MASLD is associated with the development of MASLD
and its effects on the gut microbial community. This study also
confirms the correlation between the development of MASLD and gut
microbes. A Chinese cohort study reported that
high-alcohol-producing Klebsiella Pneumoniae (HiAlc-Kpn), which
produces large amounts of alcohol, was detected in 61% of MASLD
patients. In order to investigate the relationship between HiAlc
bacteria and fatty liver disease, they fed specific pathogen free
(SPF) mice with HiAlc-Kpn. It is noteworthy that HiAlc-Kpn feeding
induced chronic hepatic steatosis. They investigated the
relationship between intestinal flora imbalance and severe MASLD
lesions (MASH and fibrosis) and showed that an increase in the
number of Ruminococcus was positively associated with an
aggravation of the degree of fibrosis (76). In addition, LPS is an important
component of the cell wall of Gram-negative bacilli. It is
recognized by pattern receptors and mediates the LPS-CD14-TLR4
signaling pathway, which activates intrahepatic KCs. These KCs
release large amounts of cytokines, such as IL-6, CD68 and TNF-α.
LPS also causes inflammation and metabolic disorders in
vivo, including increased fat burning, elevated circulating
free FFA and TG and deposition of FFA in the liver. This process
may contribute to inflammation and trigger IR, which can ultimately
lead to MASLD. The deposition of FFA in the liver may also promote
inflammation, leading to IR, which in turn triggers the development
of MASLD (77). Dysbiosis may
also contribute to MASH through other mechanisms, such as ethanol
production and interference with choline metabolism (22). Overall, intestinal flora and its
harmful metabolites (including EtOH, SFA, polyamines and
H2S) may be drivers of liver injury (76).
BA is synthesized in the liver and the main raw
material for synthesis is cholesterol. BA regulates glucose and
lipid metabolism. BA, along with its downstream receptors farnesoid
X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5),
plays an important role in lipid metabolism in the liver (78). BA also regulates the cholesterol
metabolic pathway, allowing cholesterol to be eliminated as a
water-soluble product and impaired regulation can lead to an
inflammatory response that can exacerbate the development of MASLD
(79). In a MASLD mouse model,
Jiang et al (80) found
that the administration of antibiotics to mice on a high-fat diet
reduced triacylglycerol accumulation in the liver. Activation of
TGR5 by BA in brown adipose tissue and muscle increases energy
expenditure and reduces diet-induced obesity (81). Activated TGR5 can downregulate
the expression level of inflammatory factors, promote energy
expenditure in adipose and muscle tissues and regulate the body's
immunity, which has a positive effect on improving MASLD (82). Watanabe et al (83) found in an animal experiment that
cholesterol and TG levels were markedly elevated in mice lacking
FXR in vivo. FXR has a positive effect on lipid regulation
and also reduces the generation of inflammatory responses; FXR
plays a key role in the regulation of BA and regulates lipid
metabolism. In addition, BA can affect the growth of bacteria and
is a bacteriostatic substance. Conversely, intestinal flora can
also regulate BA, intestinal flora and BA metabolism affect each
other. However, the effects of different flora are inconsistent.
For example, Aspergillus and Anaplastic bacilli in
the intestine will reduce the synthesis of BA and aggravate
inflammatory reactions, while Actinobacteria will increase
the synthesis of BA, reduce the inflammatory response and reduce
the damage of hepatocytes (84).
The normal metabolism of BA plays a crucial role in maintaining the
balance of intestinal flora. Gut microorganisms can also accelerate
the metabolism of primary BA and produce secondary BA, increasing
BA types (85). LPS produced by
intestinal flora can stimulate NF-κB to recruit inflammatory
factors and increase the level of inflammation in the body. These
studies suggest that influencing the gut flora by modulating the
signaling pathways between BA and their controlled receptors is a
promising new therapeutic approach for the treatment of MASLD
(86).
Phenotypic changes in LSEC are one of the key events
in the progression of MASLD in humans, suggesting that the
progression of MASLD inflammation, hepatic fibrosis and impaired
hepatic lipid metabolism may affect the expression of Fc γ receptor
IIb (FcγR IIb) and macrophage function in LSEC (87). Autophagy is an intracellular
process that maintains homeostasis in vivo by forming
double-membrane autophagosomes that encapsulate to-be-degraded
material and bind to lysosomes to self-digest excessive or
defective organelles. Autophagy can be categorized into three
types: Macroautophagy, microautophagy and molecular
chaperone-mediated autophagy, of which the most common is
macroautophagy. Autophagy is related to MASLD and macroautophagy is
the main type of autophagy that regulates MASLD. Liver autophagy is
defective and autophagy level is reduced in MASLD patients and
autophagy shows different functions at different stages of MASLD
(87). In the early stage of
MASLD, autophagy inhibits apoptosis (87), while in the late stage, autophagy
is pro-apoptotic, which also indicates that autophagy is involved
in the whole stage of MASLD development (87). Recombinant autophagy-related
protein 7 (Atg7), a core member of the anti-thymocyte globulin
(ATG) gene family, is responsible for driving the classical
degradation and the major stages of autophagy, which is a key
component of the autophagy-associated gene family. Abnormal
expression of Atg7, a core member of the ATG gene family, can drive
the main stage of classical degradation of autophagy, resulting in
defective autophagy in cells. In Atg7 knockout mice, hepatic
autophagy activity was markedly reduced and intracellular lipid
accumulation was increased, leading to the formation of MASLD
(88). Phosphatidylinositol-3
kinase (PI3K) is a key regulator of the activation of the mammalian
target of rapamycin (mTOR), which is considered an important
regulator upstream of the ATG gene. The PI3K inhibitor
3-methyladenine blocked the formation of autophagosomes, increased
the lipid content of hepatocytes and promoted the formation of
MASLD (89).
Inflammatory response induced by immune system
dysfunction has been found to be one of the hallmarks of MASH and a
progressive form of MASLD (90).
Under normal conditions, the liver has immune defense and
immunoregulatory functions and when the intensity of the immune
system's response to autoantigens exceeds the limits of immune
regulation and affects its physiological functions, it will cause
inflammatory damage to its tissues or organs, leading to the
occurrence of autoimmune diseases. The liver has a large number of
immune cells involved in the immune response and it has been found
that macrophages are the largest proportion of immune cells
(80-90%) in the human liver and they are closely related to the
development and severity of MASLD (91). In patients with MASLD, macrophage
infiltration occurs around the portal vein and is observed at an
early stage before evidence of inflammation appears. In addition,
macrophages are capable of producing a variety of inflammatory
factors, such as NF-κB, TNF-α, IL-2, IL-6 and IL-8 and activating
nuclear transcription factors like NF-κB, which also play an
important role in the progression of MASLD (92). NF-κB, as a nuclear
transcriptional regulator of inflammatory genes, which is
activated, enters the nucleus and promotes the transcription and
expression of inflammatory factors, releasing a large number of
inflammatory factors. After entering the liver, NF-κB leads to
oxidative stress in hepatocytes, activates the expression of
pro-apoptotic proteins in mitochondria, promotes hepatocyte
apoptosis and exacerbates the progression of MASLD (93). TNF-α is one of the important
regulators mediating hepatocyte injury and is also a bridge between
inflammation and metabolism that plays a key role in the
development of MASLD. TNF-α regulates the inflammatory signaling
pathway and exacerbates the inflammatory response in MASLD through
pathways such as NF-κB and p38 mitogen-activated kinase (94). IL-2 can promote the proliferation
of activated B cells and is also a growth factor for all T cell
subpopulations and can positively feedback regulate the production
of cytokines such as TNF-α, leading to a further increase in IL-2
in MASLD livers (95). IL-6 can
inhibit the activity of lipoprotein esterase, which can reduce the
ability to catabolize lipids and promote the formation of hepatic
lipids. IL-8 can cause inflammatory cells to accumulate in the
liver and cause inflammation and lipid accumulation in hepatocytes
can also stimulate the inflammation of MASLD hepatocytes. The
accumulation of lipids in hepatocytes can also stimulate KCs to
release TNF-α, which further promotes the production of IL-8 and
participates in the inflammatory response of hepatocytes, leading
to the aggravation of hepatocyte injury (96).
Genetic biomarkers for MASLD include DNA sequence
variants, such as single nucleotide polymorphism (SNP) and the most
studied SNPs in MASLD are rs738409 and rs58542926, which are
located in patatin-like phospholipase domain containing protein 3
(PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2),
respectively. The risk of developing MASLD has been found to be
influenced by single nucleotide gene polymorphisms. For example,
SNPs in the PNPLA3 gene and mutations in the PNPLA3 gene are
associated with MASLD. PAPLA3 is one of the members of the
patatin-like phospholipase family that have been identified as
being closely associated with the development of MASLD (97,98), PNPLA3 was found to be expressed
mainly in the liver and adipocytes, with non-specific TG lipase and
acylglycerol transacylase activities involved in TG hydrolysis in
hepatocytes. Mutations in PNPLA3 antagonize normal proteasomal
degradation and increase the risk of MASLD and its severity. TM6SF2
is a multiple transmembrane protein that is involved in lipid
transfer, VLDL secretion and TC synthesis. For the rs58542926
variant of the TM6SF2 gene (E167K), a mutation in the TM6SF2 allele
results in decreased VLDL secretion and fatty acid retention in the
liver, leading to hepatic steatosis and progression of MASLD
(99). Hydroxysteroid (17-β)
dehydrogenase 13 (HSD17B13) is a gene encoding the hepatic lipid
droplet protein 17β-hydroxysteroid dehydrogenase type 13 and it has
been found that HSD17B13 expression is markedly upregulated in
patients and mice with MASLD, suggesting that HSD17B13 usually
produces a product that promotes hepatocyte injury (100). Other SNP genes associated with
MASLD include neuromucin and glucokinase regulatory protein. In
addition, the level of immunity and metabolic rate of an individual
are genetically related.
MicroRNAs are a class of RNA regulators, ~22
nucleotides in length and a growing number of studies on
diet-induced and genetic (ob/ob) models of obese rodents and
patients with severe MASLD suggest a potential role for miRNAs in
MASLD pathogenesis and IR (101). A number of miRNAs have been
identified, including miR-122 and miR-21 and their expression
levels in both peripheral blood and liver have been associated with
the development of MASLD (102). One study found that serum
miR-122 was upregulated 7.2-fold in patients with MASH compared
with healthy subjects and 3.1-fold compared with patients with
simple steatosis. This suggests that serum miR-122 is an
extra-hepatic feature of MASH. Moreover, in a mouse model without
elevated alanine aminotransferase (ALT), the elevated serum miR-122
levels were positively associated with the severity of MASLD
(103). It has been observed
that the expression level of miR-21 in the liver of diet-induced
MASH mice progressively decreased with disease progression,
compared with the control group (103). It has been found that miR-27a
attenuates neoplastic liver lipogenesis and obesity-induced MASLD
by inhibiting the fatty acid synthase (FAS) gene and stearoyl
coenzyme A desaturase-1 in the liver. Histological analyses also
showed reduced lipid accumulation in the livers of mice with
hepatic miR-27a overexpression, suggesting reduced hepatic
steatosis; furthermore, trichrome staining of miR-27a overexpressed
livers showed markedly reduced fibrosis and lower MASLD activity
scores, reflecting improved development of MASLD (104). miR-155 is one of the miRNAs
that can regulate KCs, which are involved in inflammatory processes
that control innate and adaptive immunity in alcoholic and MASLD
diseases (103). Szabo and Csak
(105) proposed that miR-155
was a major regulator of inflammation and mice lacking miR-155 on
methionine choline deficiency (MCD) with attenuated steatosis but
no change in serum ALT or inflammation indicative of liver damage
after diet-induced steatohepatitis. In another MASH model, however,
miR-155 deficiency resulted in enhanced hepatic steatosis (105). A study has found miR-16 to be
elevated in MASLD patients with simple steatosis and others have
found that serum miR-16 is elevated in MASH patients and is
associated with the stage of fibrosis (106). It has been observed that the
expression of miR-197, miR-146b, miR-181d and miR-99a is markedly
decreased in MASLD patients. Additionally, the hepatic levels of
miR-301a-3p and miR-34a-5p increase monotonically from simple
steatosis to MASH to cirrhosis. Conversely, miR-375 levels decrease
monotonically during this progression (107). Some MASLD-related miRNAs, such
as miR-149, had elevated expression levels in both FA-treated human
hepatocellular carcinomas cells and MASLD animal models (102).
Some studies have found a large number of circadian
rhythmically expressed genes in the liver, which are involved in
maintaining the metabolic balance of the body. MASLD is closely
related to daily lifestyle. Irregular lifestyle may cause liver
overload, including lack of sleep and little exercise. In addition,
long-term intake of high-fat and high-protein foods, omitting
breakfast, adding meals before bedtime and other bad dietary habits
are also risk factors for MASLD (110). Sleep deprivation leads to an
increased risk of morbidity and mortality (111). Epidemiologic studies have shown
that sleep deprivation leads to altered glucose homeostasis, IR,
weight gain, obesity, metabolic syndrome and DM, all of which are
associated with MASLD. In experimental studies, it has been found
that sleep disorders may induce MASLD through pro-inflammatory
markers such as TNF-α, IL-1β and IL-6. In addition, sleep
deprivation increases growth hormone-releasing peptide levels and
decreases LEP levels, which increases appetite and further
contributes to obesity and chronic insomnia activates the
hypothalamo-pituitary-adrenal axis, which increases stress
hormones, exacerbates IR and promotes the development of MASLD
(112,113). Another study found that
increased mRNA expression in hepatic biological clock genes, a
decrease in levels of key metabolism-regulating enzymes, hepatic
inflammation and steatosis can occur, which is associated with
glucose and fatty acid metabolism (111). In the case of liver-specific
knockout of BMAL1, which results in the loss of key metabolic gene
oscillations in the liver and subsequently exacerbates oxidative
damage to hepatocytes and induces IR. The glucocorticoid rhythm
plays a key role in coordinating glucose, lipid and protein
metabolism and it is an entrainment signal for the systemic
circadian rhythm through the hypothalamic suprachiasmatic nucleus,
the peripheral clock in the liver and adipose tissue. The kidney is
regulated by the autonomic nervous system and rhythmic entrainment
signals. It has been noted that the oscillation of the cellular
redox state, independently of the biological clock transcriptional
feedback loop and in the metabolic process, may control the
circadian rhythm (114).
Circadian rhythm disruption will lead to cellular dysfunction,
which in turn affects the metabolic function of the liver (115). It induces metabolic dysfunction
and the occurrence of obesity, fatty liver, metabolic syndrome and
other conditions.
Social stress is closely related to emotional and
physical health and one of the factors that can trigger the
development of MASLD is excessive stress (116). Some studies suggest that
emotional problems such as anxiety and depression may have an
effect on the progression of chronic liver diseases, including
MASLD (117). A study by
Youssef et al (118)
confirmed the association of depression and anxiety with the
severity of histologic features of MASLD by examining 567 patients,
demonstrating that depression was markedly dose-dependent with more
severe hepatocellular ballooning and that patients with subclinical
depression were 2.1 times more likely to develop more severe
hepatocellular ballooning than patients without depressive
symptoms.
Studies have shown that hyperinsulinemia, lipid and
lipoprotein metabolism changes caused by high-fat diet (HFD),
high-carbohydrate diet, or high-fat and high-carbohydrate diets may
promote the occurrence and development of MASLD (119). Yu et al (120) explored the relationship between
dietary choline and MASLD, choline deficiency stimulated hepatic
fat accumulation and increased dietary choline intake in
normal-weight Chinese women associated with a reduced risk of
MASLD. Soft drinks and meat intake were markedly associated with
the increased risks of MASLD (121,122). High salt intake may affect
MASLD by increasing plasma levels of triglyceride (TG) and it
intake also stimulates endogenous fructose production. Lanaspa
et al (123) found that
a high salt diet activated the aldose reductase pathway in the
liver, leading to endogenous fructose production, which induced LEP
resistance with the development of the metabolic syndrome and
MASLD. In a study based on a northern Chinese population, the
correlation between salt intake and MASLD in DM patients was
analyzed by Spearman analysis, which showed a positive correlation
between salt intake and the incidence of MASLD, suggesting that the
likelihood of MASLD in DM patients increases with increasing salt
intake (124). A variety of
mechanisms, including the anti-oxidant, anti-inflammatory and
anti-fibrotic effects of coffee, may be related to the protective
effects of coffee against MASLD (125). Studies have shown that caffeine
may stimulate the hepatic autophagy-lysosomal pathway and induce
fatty acid oxidation (126).
However, how caffeine activates autophagic flux is still unclear
(125). Active smoking has also
been associated with a high risk of MASLD and a study has
demonstrated the association of smoking history with advanced liver
fibrosis in patients with MASLD (127). A cross-sectional study of 2,691
Chinese men found that ex-smokers and heavy smokers (≥40
cigarettes/day) had a higher prevalence of MASLD than never-smokers
and some studies have reported that smoking is an independent risk
factor for MASLD, which may exacerbate MASLD (128,129).
Commonly used laboratory animals include rats, mice
and rabbits. Among them, rats and mice are the most widely used.
Rats are represented by Wistar and Sprague Dawley (SD). There are
more diverse mouse strains, with C57BL/6J being the most common.
The present study summarized rat, mouse, rabbit, monkey, chicken,
hamster and guinea pig models. The models summarized include
diet-induced models, drug-induced models, special models and
spontaneous models. Diet-induced models include HFD, MCD,
choline-deficient amino acid-defined (CDAA) and atherogenic diet.
It has the advantages of simple operation, low cost, repeatability
and low mortality, but the disadvantage is that it is
time-consuming. Drug-induced models usually use drugs such as
streptozotocin (STZ), carbon tetrachloride (CCl4), LPS
and tetracycline. Their advantages are short modeling time and
economy, while its disadvantages are that the drugs have high
toxicity. Special models mainly use gene knockout methods to make
model animals prone to fatty liver. Compared with other models, the
modeling time of spontaneous formation of fatty liver in special
models is short, but it has requirements for the variety of animals
and high cost. Spontaneous models mainly include monkeys. Monkeys
are similar to humans in genes and can develop MASLD in old age
without the need for a high-fat diet or drug induction. The
modeling method of the nutritional model is to feed laboratory
animals with high-sugar, high-fat and high-calorie diets or to
create an MCD. The drug-induced model aims to build the model by
administering drugs such as CCl4, tetracycline,
polychlorinated biphenyl 118, so that the drugs exert their effects
or even cause poisoning. The special strain model is to select
certain diseases that can spontaneously form fatty liver,
hyperlipidemia and other diseases closely related to MASLD or can
spontaneously present symptoms relates to MASLD. The aforementioned
modeling methods can be used independently and the pathological
characteristics or disease phenotypes of the model can be
reasonably selected according to different experimental
requirements, they can also be used in combination to reduce the
modeling time and improve the success rate of the model. The
pathogenesis of MASLD is complex and a single animal model cannot
fully mimic human MASLD. The ideal animal experimental model is a
composite model formed by combining gene mutation or specific
target gene modification with diet and drug/toxin induction. The
phenotype of such a MASLD animal model is closer to that of human
MASLD and the experimental results are more applicable to
humans.
Rats are of moderate size and have strong fertility
and blood collection abilities. Currently, commonly used rat models
for constructing MASLD diseases in laboratories include Wistar
rats, SD rats and Zucker rats (Table
I).
It is found that 93% of genomic regions of mice are
arranged in an order similar to that of human beings and they are
characterized by inexpensive feeding, rapid reproduction, easy
modeling and small inter-individual differences that facilitate the
observation of parallel experiments. MASLD mouse models can
simulate different pathogenic factors and the development of MASLD
at each stage of the disease, guide the search for the pathogenesis
of MASLD and its potential therapeutic targets and also be used for
the screening and evaluation of MASLD drugs, which are closely
related to the research of MASLD. Mouse models have been induced by
high-fat and high-sugar diets, subcutaneous injections of
CCl4 and gastrointestinal nutritional solutions, with
high-fat diets being the main modality. Mice commonly used in
current experimental studies include C57BL/6J mice, Kunming mice
and gene-deficient mice (Table
II).
In addition to rodents, other animals are commonly
used to establish MASLD models, including rabbits, monkeys and
chickens (Table III). These
models are helpful for studying the disease progression and
providing crucial evidence for exploring the pathogenesis of MASLD
and evaluating the efficacy of drugs (Table IV).
At present, animal models are the most commonly
used in the research of MASLD. However, animal models have some
unfavorable factors, such as large individual differences, long
model-building cycles, difficult control of experimental conditions
and differences between animals and humans. By contrast, cell
models are superior in overcoming the aforementioned factors.
According to experimental requirements, cell viability can be
maintained all the time, which is close to the process of human
diseases and the cellular mechanisms of diseases can be studied in
a targeted manner. Therefore, establishing a cell model of MASLD
in vitro has important theoretical significance and broad
application value for studying its pathogenesis and disease
development and further preventing and treating MASLD.
Existing model cells can be classified into human
primary hepatocytes, animal primary hepatocytes, human hepatocytes,
hepatocyte-like cells (HLCs), induced pluripotent stem cells
(iPSCs) and liver slices. The culture forms can be divided into
monoculture, co-culture and three-dimensional culture. Advantages
and disadvantages of different cell lines and different culture
methods were shown in Fig.
4.
Monoculture refers to the adherent culture of one
type of cell, which is the most basic culture method. Compared with
co-culture, monoculture has the advantages of simple operation,
unlimited subculture and short model-building time, which is
conducive to high-throughput drug screening experiments. Therefore,
it is widely used in the research of fatty liver. Human hepatocyte
cell lines, primary human hepatocytes (PHH), animal primary
hepatocytes and HLC can be used for induction culture. The
excessive deposition of extracellular matrix (ECM) leads to the
occurrence of fibrosis (194),
which is a major cause of liver function impairment. The limitation
of monoculture is that it cannot explore the cell-ECM interaction
and cannot well mimic the phenotype of liver fibrosis. The
three-dimensional liver fibrosis cell model mentioned below can
solve this problem and can also well simulate the human ECM
structure in vitro (195).
PHH is generally extracted from surgically resected
tissues and separated from the tissues by two-step collagenase
perfusion or magnetic cell separation techniques (196), which can well mimic the
physiological situation of the human liver. However, due to its
rapid dedifferentiation in vitro and the need to obtain
ethical permission for specimen acquisition, these reasons limit
the use of primary hepatocytes. The improved medium supplemented
with various chemicals solves the problem of limited traditional
primary hepatocyte culture time. The PHH cultured with this medium
can be comparable to PHH spheroids for at least 4 weeks and has the
potential to simulate steatosis disease models (197).
Due to individual differences among different
donors and the influence of various factors in the cell separation
process, the experimental results may be unstable and have poor
reproducibility. In addition, the culture conditions of human
primary hepatocytes are relatively harsh, they can only be cultured
in the short term and cannot be subcultured indefinitely, which is
not conducive to the progress of the experiment. The scarcity of
human liver samples and ethical issues also hinder the wide
application of human primary hepatocytes.
Animal primary hepatocytes are often derived from
the livers of rodents and the hepatocytes are isolated and
extracted by perfusion or non-perfusion methods. The non-perfusion
method mechanically separates and digests with collagenase or
trypsin on small pieces of liver tissue. The non-perfusion method
is simple to operate but often has the problem of incomplete
digestion, while the perfusion method can greatly improve the
viability of the isolated hepatocytes, with a survival rate as high
as 80% (198). The two-step
collagenase perfusion method is the standard procedure for
isolating primary hepatocytes. The improved standard procedure can
show higher cell viability (85-95%) through multi-parameter
perfusion control (199).
Animal primary cells solve the ethical and quantitative restriction
problems of human primary hepatocytes. However, they are affected
by different animal sources and batches, have poor reproducibility,
are relatively sensitive and have harsh cultural conditions.
HLC can be derived from embryonic stem cells,
induced pluripotent stem cells, mesenchymal stem cells, endodermal
cells and hepatic progenitor cells. Hepatocyte nuclear and
epidermal growth factors are often used to promote cell-directed
differentiation. Oncostatin M (OSM) helps to promote the maturation
of fetal hepatocytes and OSM is often added during the maturation
stage to promote complete cell differentiation. Although the
subsequent culture time of HLC is longer than that of traditional
PHH, its induction time is long (2-4 weeks) and the cost is high
(200). There is also no
unified standard for the types and ratios of cytokines and
nutrients during the differentiation process and these factors
limit the application prospects of HLC.
Induced pluripotent stem cells can differentiate
into various somatic cells without causing immune rejection and
ethical issues. The HLCs differentiated from human iPSCs can be
comparable to primary hepatocytes in terms of morphological and
functional characteristics and have the advantages of wide sources,
large cultivation quantities and stable phenotypes, making up for
the deficiencies of primary hepatocytes (204). However, the induced pluripotent
hepatocyte technology still has problems, such as low efficiency of
inducing cell transformation, possible gene mutations during the
induction process and tumorigenic risks, which limit its wide
application.
The co-culture model can make up for the defects of
the monoculture model. Introducing a second type of cell into the
model increases the interaction between cells and can offer an
improved simulation of the physiological functions of the liver.
The advantages of the co-culture model are that it compensates for
the shortcomings of the monoculture model, has simple culture
conditions and enables high-throughput experiments. However, there
are not a great number of existing co-culture model types and there
is great potential for future development. Chen and Ma (205) established a co-culture model of
HepG2 cells and THP-1 macrophages. Firstly, the macrophages adhered
to a sterile glass slide and then the slide was placed into a
6-well plate inoculated with HepG2 cells. A mixed fatty acid with a
concentration of 1 mmol/l (the ratio of PA:OA was 1:2) was added
and an MASLD model was established after 24-h induction. Giraudi
et al (206) co-cultured
HuH7 and human hepatic stellate cells. After 24-h induction with
fatty acids, the intracellular lipid accumulation increased and the
expression of α-smooth muscle actin increased, indicating that the
hepatic stellate cells were activated and the cells showed the
characteristics of steatosis and fibrosis. In another study, human
primary hepatocytes, hepatic stellate cells and KCs were
co-cultured. The cells were stimulated with fatty acids, glucose,
insulin and inflammatory cytokines to simulate MASH. In this model,
the de novo lipogenesis in the cells was enhanced and the
cells showed symptoms of oxidative stress, inflammation, fibrosis
and activation of hepatic stellate cells (207). The co-culture of human primary
hepatocytes and endothelial cells can support hepatocytes to
maintain their phenotypic morphology, improve their specific
functions and form capillary-like structures, which is more
conducive to simulate the in vivo environment and studying
the pathological mechanisms of fatty liver disease (208).
In the living liver tissue, there is substance
transport and signal transduction between hepatocytes and the ECM
and the ECM also plays a role in supporting the three-dimensional
structure (209). When human
primary hepatocytes are cultured in the traditional two-dimensional
system for a long time, morphological changes occur due to
epithelial-mesenchymal transition, resulting in the loss of
hepatocyte polarity and related liver functions (210). The construction of a
three-dimensional model is more complicated. For the
three-dimensional model of PHH, KCs and hepatic stellate cells
co-cultured with the help of a three-dimensional microphysiological
system, at least two weeks of induction with FFA is required
(211). The co-culture mode
with multiple hepatocytes can more accurately simulate the liver
microenvironment, but it requires more stringent culture
conditions. In the case of few or no precedents, researchers are
required to preliminarily explore the culture medium suitable for
the survival and proliferation of multiple cells, at least
considering the effects of pH value, osmotic pressure and gas
environment. Three-dimensional culture is divided into
three-dimensional monoculture and three-dimensional co-culture.
The three-dimensional co-culture model can be used
to study more complex fatty liver phenotypes, such as inflammation
and liver fibrosis. In the three-dimensional co-culture model,
human hepatocytes are cultured together with non-parenchymal cells,
which can simulate the interactions between various types of cells
in the liver in three-dimensional space. The advantage of the
three-dimensional co-culture model is that it can maintain
important metabolic functions for a long time and induce fatty
liver pathological phenotypes under relevant conditions.
Hepatic spheroids are spheres formed by the
self-aggregation of hepatocytes cultured in suspension without a
substrate-promoting cell attachment. The size of the spheroids can
be controlled by changing the number of starting cells and this
controllability provides convenience for standardized measurement.
The cell sources for hepatic spheroid culture can be primary
hepatocytes, hepatocyte cell lines and induced pluripotent stem
cells. Single-cell and multi-cell cultures can both form hepatic
spheroids. Compared with the planar culture of cells, the
three-dimensional structure presents superior characteristics of
the liver. HepG2 cell spheroids are more sensitive to hepatotoxic
substances. Compared with HepG2 cells cultured in a monolayer, the
half-maximal effective concentration values of a number of drugs
are markedly reduced (213).
Hepatic spheroids cultured from PHH can survive up to 7 weeks
(214) and can achieve 100%
specificity and 69% sensitivity in distinguishing hepatotoxic
substances (215). Compared
with hepatic spheroids derived from single-cell culture, multi-cell
co-culture spheroids may have more development potential. Hepatic
spheroids constructed by co-culturing PHH and NPC perform
outstandingly in glycogen storage (216) and albumin synthesis, indicating
that co-culture hepatic spheroids can offer an improved imitation
of the structure and function of the human liver (217).
Organoids have a self-renewing stem cell population
and can exhibit some organ characteristics, which contain single or
multiple cell types. It has been reported that organoids from adult
hepatocytes can be cultured for up to 2.5 months (218). PHH and pluripotent stem cells
can both simulate the adult liver. For the induction of pluripotent
stem cells, a three-dimensional model can be constructed after
monolayer culture induction to maturity or directly cultured in
three dimensions at the undifferentiated stage (219). The induction of MASLD requires
the addition of FFA to the culture medium. Liver organoids in this
hepatotoxic environment for a long time show lipid droplet
formation and TG accumulation and the upregulation of the
expressions of genes related to lipid metabolism, inflammatory
cytokines and fibrosis markers, showing the typical biochemical
characteristics of MASLD progression (220). In addition, liver organoids can
also be derived from liver cancer cells to simulate the cancer
microenvironment, playing an important role in the field of
anti-cancer research.
Liver-on-a-chip technology is used to simulate the
minimum functional unit of liver tissue, mainly constructed with
the assistance of computer aided design software. When designing a
microfluidic chip, factors such as flow rate, design size and
aspect ratio need to be considered. In a three-dimensional culture
system, microfluidic devices can reproduce the characteristics of
the multi-cell microenvironment by controlling various parameters
(221) and conducting cell
culture and sample secretions. Although liver-on-a-chip technology
is costly and the chip manufacturing process is complex, it can
mimic the complex in vivo liver microenvironment, precisely
control chemical gradients and manipulate parameters such as time,
so it has broad development prospects in the research field of
cell-matrix and cell-cell interactions.
3D-bioprinting technology polymerizes various
biological materials through inkjet, extrusion, laser
polymerization, or digital light processing. In the field of liver
model construction, a vascularized hepatic lobule model containing
hepatocytes and endothelial cells has been developed through
extrusion technology. Compared with a simple mixture of hepatocytes
and endothelial cells, this model has increased albumin and urea
secretion and a superior imitation of liver functions (222). With the development of
3D-bioprinting technology, the optimization of 'ink' has also been
put on the agenda. Type I collagen is the main component of the
ECM. When collagen I is mixed with thiolated hyaluronic acid in
different ratios, it was found that the ratio of 3:1 can offer an
improved maintenance of biological activity (223). The bioprinting method for MASLD
needs to be further explored. One possible idea is to culture
monolayers of steatotic hepatocytes as 'ink' to print
three-dimensional structures or to induce lipotoxic substances
after printing a liver model (224,225).
The chronic stress method uses one or several
stress factors to change the emotional state of experimental
animals (226). Although this
method has a good effect, it takes a long time and only one
emotional stimulus is applied to the rats for a long time, which is
likely to cause the rats to adapt to the stimulus, resulting in
insignificant emotional changes. To improve the errors caused by
this method, unpredictable stress is now mostly used in the
experiment, which can minimize errors and prevent rats from
adapting to the stimulus. Sun et al (227) used fixed-time foot electroshock
combined with noise stimulation to increase the diversity of
chronic stress methods.
The chronic restraint method is a way to restrict
the activities of experimental animals by placing them in restraint
devices, thus triggering emotional changes in the experimental
animals. Some scholars have established the MASLD model by using
long-term chronic restraint stress. They mainly applied restraint
stress to rats by using plastic restrainers. To prevent the rats
from breaking free, they also carried out punctures multiple times
to make the restrainers fit closely with the rats. The rats were
restrained for 6 h every day and this lasted for 9 weeks (228-231).
Since MASLD is a chronic disease, according to the
theory that chronic diseases often lead to deficiency and blood
stasis, patients with this disease usually present with various
syndromes of deficiency and blood stasis, among which the syndrome
of blood stasis is the most common. Patients with this syndrome
show symptoms such as masses in the right hypochondrium, loss of
appetite, abdominal distension, weakness, loose stools, dull
complexion and a pale and dark tongue. Liu et al (232) prepared the MASLD model of blood
stasis syndrome by feeding rats with a high-fat and HFFD and
intraperitoneally injecting 30 mg/kg STZ. The results showed that
the rats' body weight firstly increased then decreased. Their fur
was yellowish, dull, wilting and lacking luster. Their mental state
was poor, they were inactive and easily startled and their claws
were dull and had a low temperature. Moreover, the levels of ALT,
AST, TC, TG and LDL-C in rats were increased and there was
inflammatory infiltration in the cytoplasm of hepatocytes.
Researchers have prepared the MASLD model of blood stasis type by
using high-fat feed combined with leg-binding stimulation and
reagent intervention methods. After 8 weeks, the rats showed
manifestations such as dull hair and irritability, an increased
liver index, diffuse fatty hepatocytes, varying degrees of
macrovesicular and microvesicular steatosis and occasionally
inflammatory cell infiltration. Meanwhile, they also had
pathological manifestations consistent with MASLD (233).
In the process of treating MASLD, since the changes
in liver tissue of most patients are at the stage of simple
steatosis, the priority of treatment should be to solve the problem
of overweight and improve the patient's IR. The secondary aim is to
avoid 'additional blows' leading to MASH and acute liver failure
and to reduce hepatic fat deposition in patients (234). Currently, the main clinical
drugs for MASLD are lipid-lowering drugs, insulin sensitizers,
anti-fibrotic and thyroid hormone drugs. Moreover, inhibition or
reduction of microRNA activity by targeted drugs can alleviate the
condition, which provides a new idea for the proposal of MASH
typing and the development of individualized treatment modalities
(235,236). The precise treatment of
different subtypes of MASH patients with targeted drugs is also the
development trend of future drug research (Fig. 5). The drugs for the targets in
the treatment of MASLD disease are shown in Table V.
Lipid metabolism disorder is the main clinical
characteristic of MASLD patients and it is an important factor in
the development of MASLD to hepatitis and cirrhosis, so
lipid-lowering has become an important method of treatment for
MASLD patients. At present, the best lipid-lowering effect of drugs
is from statins, their mechanisms are mainly through the inhibition
of hydroxy methylglutaryl coenzyme A (HMG-CoA), thereby blocking
the synthesis of hepatic cholesterol and causing hepatic
compensatory LDL receptor synthesis, so that the plasma LDL and LDL
clearance increases. At the same time, statins can also exert
anti-oxidant and anti-inflammatory effects (237). However, there are more problems
in the use of statins, such as producing hepatotoxicity and muscle
toxicity (238). In recent
years, it has been found that inhibition of proprotein
convertase-subtilisin-kexin type 9 (PCSK9) can markedly reduce LDL
levels. Another experimental study found that the combination of
statins with PCSK9 inhibitors was more effective than statins alone
(239). In addition, ezetimibe
and PCSK9 inhibitors (IIb, C) can be used in combination in
statin-intolerant patients (240).
IR is a key link in the pathogenesis of MASLD,
insulin sensitizers can effectively target the 'one strike' and
increase insulin sensitivity to improve IR. Thus, enhancing the
sensitivity of effector organs to insulin has become an important
way to treat MASLD. Metformin, glucagon-like peptide-1 (GLP-1),
thiazolidinediones and other drugs are currently more popular.
Metformin contains two guanidinium groups in its
structure and is a common oral metformin hypoglycemic drug in
clinical practice. It lowers blood glucose by decreasing glucose
production in the liver, increasing glucose metabolism and thus
improving IR and has a certain effect on weight loss and regulation
of lipid metabolism (241).
However, metformin is generally not used alone in the treatment of
MASLD (242). Some studies have
shown that metformin can markedly reduce the levels of ghrelin,
insulin and C-peptide in MASLD patients, but the improvement of
liver fibrosis and liver inflammation is not significant (243,244). Although metformin is not the
first choice for the treatment of MASLD, it is effective in
improving body weight, lipids and glucose metabolism in patients
with MASLD or MASLD combined with T2DM (245).
GLP-1 is a well-established target in the field of
diabetes. Liraglutide is a GLP-1 agonist used for the treatment of
type 2 diabetes (1.2 to 1.8 mg/day) and obesity (3 mg/day). In
addition to acting on the pancreas, GLP-1 can improve peripheral
insulin sensitivity, participate in the physiological regulation of
blood glucose, increase hepatic glucose uptake and glycogen
synthesis, delay gastric emptying and reduce appetite and reduce
the occurrence of atherosclerosis (246). Several GLP-1 drugs have been
studied in clinical trials for their ability to promote insulin
secretion, induce β-cell proliferation, inhibit postprandial
glycogen release and delay gastric emptying. It has been shown that
GLP-1 receptor agonists can enhance insulin sensitivity in effector
organs, promote fatty acid oxidation, reduce lipogenesis and
improve glucose metabolism after binding to the receptor (247).
Polyene phosphatidylcholine has anti-oxidant,
anti-inflammatory properties, reduces hepatocyte damage and
apoptosis and can effectively target the pathological symptoms
caused by MASLD and its combination with metformin drugs for the
treatment of patients with MASLD as well as MASH is markedly more
effective than monotherapy (248). Obeticholic acid (OCA), as a
nuclear transcription factor FXR agonist, has good application in
the treatment of MASLD by affecting the gene expression of various
metabolic and cellular damage pathways, such as lipid metabolism,
IR and oxidative stress (249).
Pioglitazones are first-generation insulin
sensitizers, which can specifically bind and activate PPAR-γ,
improve IR, participate in glucose and lipid metabolism and inhibit
the expression of LP and the expression of TNF-α, so as to reduce
the hepatic lipid deposition and inhibit liver inflammation and
fibrosis formation (250).
Sumida and Yoneda (251) found
that pioglitazone not only improved IR but also improved hepatic
glucose-lipid metabolism, steatosis and inflammatory necrosis in
patients with MASLD by activating PPAR-γ. The American Academy of
Liver Diseases recommended pioglitazone in 2017 guidelines for the
diagnosis and treatment of MASLD (252). Pioglitazone is not widely
available because of safety concerns, including congestive heart
failure, bone fractures in women and the possibility that
pioglitazone may lead to an increased risk of bladder cancer
(253). The second-generation
insulin sensitizer MSDC-0602K did not show the side effects
associated with the first-generation insulin sensitizers. According
to the report of the latest phase IIb 52-week double-blind study
(254), MSDC-0602K markedly
reduced fasting glucose, insulin, glycosylated hemoglobin and
markers of liver injury without dose-limiting side effects.
However, it did not show a significant effect on the liver
histology of the biopsy technique used. The information gained from
this trial may provide a pre-basis for future study.
In the disease process of MASLD, increased
oxidative stress and defective anti-oxidant defense mechanisms
promote liver injury as well as disease progression to MASH
(255). Therefore, drugs with
anti-oxidant activity can be used in the treatment of MASLD.
Vitamin E is present in the phospholipid bilayer of cell membranes
and helps to prevent oxidative damage caused by free radicals
(256). The randomized
controlled trial of PIVENS selected non-diabetic and non-cirrhotic
MASH patients, conducted a 2-year trial of vitamin E (800 IU/d),
pioglitazone and placebo and showed that vitamin E had significant
histological improvements and that 36% of patients treated with
vitamin E had improved steatosis, inflammation and remission of
MASH (257). This suggested
that vitamin E is favorable for the treatment of MASLD and MASH
(258). However, long-term use
of vitamin E may increase the risk of prostate cancer and
hemorrhagic shock, so vitamin E should not be used for long-term
treatment of MASH and MASLD (259). Another study found that the
active ingredient in silymarin could improve liver fibrosis and
reverse MASLD by reducing oxidative stress and inflammation
(260). Although silymarin did
not meet the primary endpoint in MASH patients, it markedly
improved liver fibrosis compared with placebo (260).
ZSP1601 is a pan-phosphodiesterase inhibitor, which
is the first small molecule innovative drug to obtain clinical
trial approval for the treatment of MASH in China. Phase Ia
clinical trials were conducted in healthy populations and ZSP1601
had a peak time of 1.5-2.5 h and a half-life of 6.34-8.64 h. The
drug was well tolerated when compared with the placebo group
(261). Its safety and
pharmacokinetic profile supports further efficacy assessment in
MASH patients. In the Ib/IIa clinical trial, ZSP601 was shown to
have a favorable safety and tolerability profile in MASH patients,
with a pharmacokinetic profile consistent with that of healthy
subjects. After receiving 28 days of treatment, different dose
groups of ZSP601 showed significant improvements in metabolism,
hepatic fat content, inflammation and fibrosis biomarker indices
(262), supporting the
evaluation of its long-term safety and efficacy in a larger sample
size of MASH patients.
Apoptosis is closely related to the formation of
hepatic fibrosis, hepatocyte apoptosis releases excessive DNA
fragments, which stimulates hepatic stellate cell activation and
promotes the formation of fibrosis. In the liver, TNF mediates a
number of biological reactions, reduces oxidative stress and fights
against fibrosis and it is a potential therapeutic drug for MASLD.
Pentoxifylline has been suggested as a potential therapeutic agent
for MASH because of its ability to reduce oxidative stress
production and its anti-fibrotic effects. Researchers treated
patients with biopsy-proven MASH with either placebo or
pentoxifylline 400 mg/day for 1 year in a small RDBPCT clinical
trial (263). The results
showed an improvement in histologic features in 38.5% of the
subjects in the pentoxifylline treatment group (13.8% in the
control group, P=0.036).
Apoptosis signal-regulating kinase 1 (ASK1) is a
kinase in the MAP3 kinase family that activates the p38/JNK pathway
downstream of TNF-α, leading to apoptosis and fibrosis. Studies in
mice have shown that ASK-1 promotes TNF-α-mediated IR and steatosis
(263), whereas inhibition of
ASK1 ameliorates diet-induced steatosis and fibrosis (264). GS-4997 is an oral ASK1
inhibitor and a randomized, double-blind, open phase II clinical
trial in patients with MASH and fibrosis is currently underway to
evaluate the efficacy of 24 weeks of treatment with GS-4997 or
GS-4997 and simtuzumab. ASK-1 inhibitors have been shown to improve
inflammation and fibrosis in animal models of MASH, but
Selonsertib's phase III trial does not meet its primary endpoint
(265).
C-C motif chemokine receptor 2/5 (CCR2/5) are
inflammatory chemokine receptors that are highly expressed in MASH.
Chemokines induce cell migration in the direction of increased
chemokine concentration and exert their biological effects by
interacting with G-protein-linked transmembrane receptors. CCR2 on
the surface of macrophages promotes inflammation,
neovascularization and activation of hepatic stellate cells,
exacerbating hepatic fibrosis, whereas CCR5 is mainly expressed by
hepatic stellate cells, causing hepatic fibrosis (266). Inhibition of the activity of
such receptors can reduce the inflammatory response in the liver
and prevent or slow down liver fibrosis. Cenicriviroc (CVC) is an
orally potent dual inhibitor of CCR2/5, which has been shown to
ameliorate the progression of hepatic fibrosis in MASH mice
(267). A phase IIb clinical
trial with a sample of MASH patients showed that the anti-fibrotic
results of CVC in the second year were consistent with those of the
first year and remained significant in the two-year treatment
group, demonstrating good tolerability and efficacy (268). CVC was in a phase III clinical
study (AURORA, NCT03028740) aimed at evaluating its efficacy and
safety in adult MASH patients with hepatic fibrosis (269). However, the AURORA phase III
trial was forced to be terminated prematurely due to the failure to
meet the objectives of its first phase results.
Elafibranor is an agonist of PPAR-α and PPAR-δ.
Studies have shown that elafibranor has the effect of improving
insulin sensitivity, balancing blood glucose, regulating lipid
metabolism and reducing inflammatory response (270). Ratziu et al (271) conducted an international,
multicenter, randomized, double-blind, placebo-controlled study to
evaluate the safety and efficacy of elafibranor in patients with
MASH. MASH patients without cirrhosis were randomized in a 1:1:1
ratio to receive elafibranor 80, 120 mg, or placebo for 52 weeks.
Liver biopsies, as well as clinical and laboratory evaluations,
were performed on patients every 2 months. The results of the
available studies suggest that elafibranor 120 mg/day for 1 year in
moderate-to-severe patients may alleviate MASH fibrosis.
The degree of hepatic fibrosis is used to determine
the progression of MASLD and most targeted clinical trials end in
the improvement of fibrosis. In addition to acting on the
pathogenesis of MASLD, some anti-fibrotic drugs have great
potential. It has been shown that activation of HSCs can exacerbate
the degree of hepatic fibrosis (272). Galactose lectin-3 (Gal-3)
protein is closely associated with inflammation and liver fibrosis.
Inhibiting Gal-3 can markedly reduce the symptoms of liver fibrosis
in animals and clinical trials have also shown that it has an
improved therapeutic effect on subjects with MASH and bridging
fibrosis (273). Pirfenidone is
a TGF-β inhibitor, clinically used in the treatment of idiopathic
pulmonary fibrosis and another study found that it markedly
improved the pathological features of liver fibrosis in animals
(273). Belapectin (GR-MD-02)
is a Gal-3 inhibitor developed by Galectin Therapeutics. Gal-3
protein is involved in a variety of inflammatory and fibrotic
processes. Animal studies have demonstrated that Belapectin reduces
fibrosis. Clinical trials have also demonstrated that it is well
tolerated in subjects with MASH with bridging fibrosis and has
beneficial prevention and treatment of esophageal varices in
patients with MASH liver cirrhosis (273).
Dysbiosis of intestinal flora is closely associated
with liver disease and cancer (274). Thus, manipulation of the
microbiome through diet, probiotics, prebiotics and other
medications is a viable line of research for the treatment of liver
diseases, including MASLD. It has been found that prebiotics can
reduce the accumulation of TG in the liver by decreasing the
production of fat and decreasing the expression of genes such as
FAS (275). In addition,
probiotics can repair leaky gut and delay the progression of NAFL
to MASH by modulating nuclear receptor expression and improving IR
in liver and adipose tissue (276). In a clinical study by
Malaguarnera et al (277), Bifidobacterium bifidum
was found to markedly improve lipids, IR index, liver tissue
inflammation and liver fibrosis in patients with MASH. Wang et
al (278) found that
Bifidobacterium trifidum tablets markedly reduced the levels
of lipids, inflammatory factors, LPS and lipocalin in a rat model
of MASH. Triclosan is a widely used antibiotic that ameliorates the
ecological dysbiosis of the gut microbiome associated with MASLD by
inhibiting pathogenic gram-negative bacteria. Solithromycin is a
new-generation macrolide antibiotic clinically used to treat
bacterial infections. In a mouse model of MASH induced by both diet
and STZ, solithromycin was shown to ameliorate hepatocellular
ballooning and inflammation, reduce blood glucose levels and
downregulate hepatic gluconeogenic enzyme expression (279). Based on preclinical results, a
Phase II open clinical trial study is currently underway to
evaluate whether 13 weeks of solithromycin treatment in
non-cirrhotic MASH patients can improve liver histologic
characteristics.
Thyroid hormone receptor (THR-β) is highly
expressed in hepatocytes and plays a key role in regulating the
impaired metabolic pathway of MASH (280). The degree of hepatic
hypothyroidism is higher in patients with MASH (281). This suggests that hepatic
hypothyroidism may contribute to the development of MASH to some
extent. Moreover, drugs targeting this condition are currently
approved for MASH treatment.
Resmetirom is an oral, liver-targeted THR agonist,
which is 28-fold more selective for THR-β than triiodothyronine for
THR-α (282). In MASH,
Resmetirom's selectivity for THR-β contributes to hepatic-mediated
thyroid hormone metabolism while avoiding the adverse effects of
excess thyroid hormones in the heart and bone mediated through
THR-α. Resmetirom and other thyroid hormone analogs reduce hepatic
TG, inflammatory factors, fibrosis markers and ALT levels and
reduce hepatic steatosis lipid peroxidation (283). In a multicenter, randomized,
double-blind, placebo-controlled Phase III clinical trial of
MAESTRO-MASH, the proportions of patients who achieved the primary
endpoint of MASH symptom resolution without worsening of hepatic
fibrosis at 52 weeks were 25.9 and 29.9% in the Resmetirom 80 and
100 mg dosage groups, respectively, compared with 9.7% in the
placebo group (P<0.001). In addition, there were significant
reductions in several lipid and lipoprotein metrics, including the
key secondary endpoint of LDL-C (284). This trial was the first phase
III clinical trial to achieve the two primary endpoints proposed by
the FDA in patients with MASH. Accordingly, based on these key
clinical data, the FDA approved the drug on March 15, 2024, for the
treatment of patients with non-cirrhotic MASH with moderate to
advanced liver fibrosis. This is the first MASH treatment approved
by the FDA and represents a landmark breakthrough in the field.
VK2809 is another THR-β selective agonist with
specificity for liver tissue and good therapeutic potential. It
belongs to a family of prodrugs that cleave and release potent
thyroxine analogs in vivo. A randomized, double-blind,
multicenter and placebo-controlled phase II study was conducted to
evaluate the efficacy, safety and tolerability of VK2809 in
reducing LDL-C and liver fat content in patients with primary
hypercholesterolemia and MASLD (285). Patients were dosed for 12 weeks
and subsequently discontinued for 4 weeks. Results showed a
statistically significant 53.8% median reduction in liver fat in
patients using 5 mg of VK2809 daily, 88% of cases in patients using
VK2809 showed ≥30% reduction in liver fat at 12 weeks. In all dose
groups, VK2809 had a favorable safety and tolerability profile,
with no adverse reactions reported.
Medicinal plants have important advantages in
preventing and improving MASLD, so treatment of MASLD by medicinal
plants is a potential therapeutic means (286). Medicinal plants have a history
of several hundred years in the prevention and treatment of liver
diseases. Compared with chemical pharmaceuticals, medicinal plants
have a holistic concept and the idea of diagnosis and treatment,
which is the most significant and basic feature of medicinal plants
and shows its advantages in the treatment of MASLD (287). The treatment of MASLD by
medicinal plants focuses on the holistic theory of liver
preservation, which manifests itself in a variety of mechanistic
forms, including anti-oxidative stress, lipid metabolism
regulation, anti-inflammation, anti-fibrosis and intestinal
microbiota regulation (288).
It can be seen that the treatment of MASLD by medicinal plants is
more individualized and comprehensive, which is in line with the
characteristics of MASLD (Fig.
5).
Single medicinal plants have multi-component,
multi-target and multi-dimensional effects in anti-MASLD. Exploring
the monomers of medicinal plants for the treatment of MASLD studies
have found that natural compounds such as polysaccharides,
terpenoids, glycosides, alkaloids, flavonoids, phenols and other
natural compounds have a wide range of biological activities. By
regulating various signaling pathways, they can exert comprehensive
benefits such as inhibiting inflammatory response, improving lipid
metabolism, reducing IR, then effectively alleviating the symptoms
of MASLD. A summary of some studies on the prevention and treatment
of MASLD by medicinal plants is shown in Table VI.
Based on evidence-based treatment, medicinal plants
combine different chemical components for specific etiology and
pathogenesis and exert the advantages of multi-targeting and
synergistic effects in the prevention and treatment of MASLD. The
mechanisms are summarized in the following Table VII.
Non-pharmacological treatments for MASLD are mainly
life-related initiatives. In general, weight control, improved
dietary patterns and lifestyle modifications can prevent the
development of metabolic syndrome and MASLD (374). Proper aerobic exercise with
intermittent high-intensity exercise can effectively reduce excess
body fat. Hannah and Harrison (375) found that MASLD patients' weight
loss of 3-5% slowed down the process of fatty liver lesions, weight
loss of 5-7% may result in reversal of fibrosis. Obese and diabetic
patients are more likely to plan their diets reasonably, adjust
their daily routines and reduce their calorie intake to prevent
MASLD at source (Fig. 5).
Dietary management should follow the principles of
nutritional balance, limiting energy intake and adjusting dietary
structure. Firstly, to supplement dietary fiber and minerals: Eat
more food rich in low calorie, high protein and high fiber, mix
coarse and fine grains and choose more vegetables, fruits, fungi
and seaweed to ensure sufficient fiber intake and maintain
intestinal microbial homeostasis. Secondly, to supplement vitamins
and appropriate amounts of micronutrients: eat more food rich in
vitamins and micronutrients selenium (purple cabbage, beans,
seafood and seaweed) can accelerate the decomposition of lipid
peroxidation and prevent liver fibrosis (376). Reduce the intake of
carbohydrates: Eat less high sugar, high fat, high cholesterol,
spicy, fried and salty food. In order to reduce the degree of
obesity and promote the oxidation and decomposition of fatty acids,
reduce the content of FFA and the burden of fat accumulation on the
liver (377). In addition,
fasting therapy: Patients only drink a moderate amount of water and
eat low-calorie food for a certain period of time, plus a moderate
amount of exercise to prevent and control MASLD, usually not more
than 10 days. After the fasting period, the use of food from soft
and easy to digest food gradually over to ordinary meals. For
patients with fatty liver caused by excessive weight loss, food
containing unsaturated fatty acids can be given to increase satiety
and nutrition according to the patient's own situation and their
fat intake should not exceed 30% (378). In other aspects: Develop good
dietary habits, eat three meals a day regularly and quantitatively,
avoid overeating diet, regular breakfast, reduce the number of fast
food and dinner, drink more tea and coffee.
Exercise training therapy is an effective means to
promote the recovery of MASLD patients, which has advantages of
being green and inexpensive. Aerobic exercise can improve the rate
of fat oxidation, increase fat consumption and reduce the
accumulation of liver fat (379). At present, with the social and
economic development and the increase of pressure at work, people
are physically and mentally exhausted. It is easy to occur a
variety of chronic diseases due to less exercise training or
insufficient continuity, so it is more important to guide the MASLD
patients to engage actively in exercise training. Li et al
(380) used exercise training
to intervene in MASLD, 3 times a week, each time lasting 3-4 times,
lasting 40-60 min and the continuous intervention for 24 weeks,
which could effectively improve the lipid metabolism level of
patients with mild, moderate and severe MASLD, reduce blood glucose
and improve the function of the liver.
Anxiety, depression and other negative emotions
will increase the risk of MASLD (381). Therefore, patients should
always maintain a stable state of mind, guard against arrogance and
impatience, combine work and rest and learn to apply exercise,
music, muscle relaxation in daily life and other methods to
alleviate their own negative emotions, relax the body and mind and
ultimately to achieve the effect of liver detoxification and
restoration of liver function.
Circadian rhythm disorders can cause MASLD, so
patients should develop good living habits, including go to bed
early, get up early, not stay up late, regular personal work and
rest. At the same time, regular checks of blood glucose, blood
lipids, blood pressure and abdominal ultrasound, in order to timely
detection of the occurrence of MASLD and its risk factors (381).
As a complex metabolic disease involving multiple
liver injuries, the incidence of MASLD is not only increasing year
by year, but also tends affect younger and younger individuals, so
its prevention and treatment should not be postponed. The
pathogenesis of MASLD is complex and progressive, the liver
histopathological diagnosis of MASLD is difficult to achieve in
humans and suitable experimental models must be established to
study MASLD, thus posing great challenges to its prevention and
drug development. The present study reviewed the complex
pathogenesis of MASLD, including IR, lipotoxicity, immune system
disorders inducing inflammatory responses, intestinal flora
disorders and genetic factors, as well as the study of Chinese
medicine on the pathogenesis of MASLD (Fig. 6). MASLD arises from the
interconnection and influence of multiple organs and systems, which
can not only act individually, but also interact and synergize with
each other to promote the development of MASLD and the specific
triggering mechanisms still need to be explored at a deeper
level.
In recent years, the study of the molecular
mechanism of MASLD has attracted much attention. The notch
signaling pathway is a highly conserved transmembrane signaling
pathway. It activates signal transduction through receptor-ligand
interactions, which affected gene expression. The Notch signaling
pathway plays a key role in hepatic lipid metabolism disorders,
inflammatory responses and liver fibrosis (382). adenosine
5'-monophosphate-activated protein kinase (AMPK), as a core hub of
energy metabolism, plays a crucial role in MASLD by regulating
fatty acid synthesis, oxidation, autophagy and inflammation.
Researches showed that various monomers of medicinal plants by
inhibiting key factors of lipid synthesis (SREBP-1c, FAS and ACC),
promoting fatty acid oxidation (PPARα and CPT-1), improving insulin
resistance, enhancing autophagy (ULK1 and LC3) and inhibiting
inflammation (NF-κB) and oxidative stress (Nrf2) (383). A large amount of basic
researches shows that the NF-κB pathway is a crucial pathway for
mediating inflammatory and oxidative stress responses and also
plays an important role in the occurrence and development of MASLD.
When the internal environment of the body changed, the levels of
inflammatory factors in the body increases markedly. The NF-κB
pathway is activated by activating the expression of inflammation
and immune related receptors on the surface of liver cell
membranes. The NF-κB pathway regulates various factors upstream and
downstream, further mediating the inflammatory response, oxidative
stress response, liver fibrosis, cell apoptosis, autophagy and
pyroptosis of liver tissue to promote the process of MASLD
(384). Chitosan markedly
improves symptoms of MASLD by inhibiting lipid production,
regulating inflammatory responses, alleviating oxidative stress,
improving insulin resistance and regulating gut microbiota through
multiple mechanisms. The specific mechanisms included that it
inhibits the expression of transcription factors, activates the
AMPK signaling pathway to promote fatty acid oxidation and inhibits
the activity of signaling pathways such as PI3K/AKT/mTOR (385).
Through the continuous efforts of researchers at
home and abroad, the study of experimental models of MASLD disease
(including animal models and cellular models) has made great
progress. Ideal disease models should be similar to human
pathogenesis, simple, inexpensive, fast modelling, low animal
mortality, high replication rate, good reproducibility and easy to
use. In the process of practical application, researchers should
understand the species differences between experimental animals and
human beings, the formation mechanism of MASLD model and
pathological changes are very different from those of human beings
when they suffer from the disease and they need to select
appropriate models according to specific research purposes and
needs and consider the complications of the MASLD model. The TCM
syndrome models, guided by TCM theory and based on the basic
principle of evidence-based treatment, has obvious advantages in
the treatment of fatty liver, but the formation principle, method
and judgement index of the model are difficult to be standardized
and need to be further verified (Fig. 6). Future research should
establish a unified standard for the models and on the basis of
improving the existing models, more efforts should be devoted to
exploring new modelling methods, so that the experimental models
can be more closely related to the characteristics of human MASLD,
with a view to carrying out more in-depth research on the disease,
elucidating its pathogenesis and an improved chance of preventing
and treating MASLD.
Due to the complex pathogenesis of MASLD, there is
no specific clinical drug and the use of a single treatment is
limited. In the light of the current research results,
individualized dietary control and lifestyle changes are the basic
treatment for MASLD. A healthy lifestyle with good dietary habits,
active treatment of the primary disease and selection of
appropriate medication as an adjuvant therapy are conducive to
intervening and controlling the development of MASLD and preventing
further deterioration of the disease. Currently, effective
therapeutic agents for MASLD are focused on multiple potential
targets, with multi-target, multi-pathway therapeutic measures and
targeted agents for key aspects of the target genes or metabolic
pathways will also be applied in the clinic. However, various drugs
are still in the research stage and in the future, clinical
attention should not only be paid to the efficacy and safety of
such drugs, but also need to further evaluate the effects of
combining drugs with different mechanisms, so as to ultimately
provide patients with a reasonable individualized medication plan
(Fig. 6). In addition to
synthetic drugs, natural medicines (TCM, Chinese medicine
compounds), are characterized by multiple components and multiple
targets of action, so the development of new natural medicines with
multiple targets of action, maintaining a healthy composition of
intestinal flora and promoting energy metabolism of the body, play
a therapeutic role in MASLD from another angle.
Not applicable.
KL was responsible for data curation and writing
the original draft. CC, LW and ZS were responsible for formal
analysis and methodology. JL, MA and QL were responsible for
conceptualization and investigation. HH, QM, XW and RW were
responsible for supervision, funding acquisition, writing,
reviewing and editing. Data authentication is not applicable. All
authors read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was supported by National Natural Science
Foundation of China (grant nos 82360682 and 82360825), Major
Science and Technology Research Projects of Nanchang City [grant
no. Hongkezi(2023)137-2], Training Project of Ganpo Juncai Support
Plan for High level and High skilled Leading Talent in 2024 (grant
no. 20240003188), 'Chunhui Plan' Collaborative Research Project of
Ministry of Education of the People's Republic of China (grant nos.
H ZKY20220385 and 202200200), Jiangxi Provincial Natural Science
Foundation (grant nos. 20242BAB26172, 20224BAB206104 and
20224BAB206112) and Jiangxi University of Chinese Medicine Science
and Technology Innovation Team Development Program (grant no.
CXTD-22002).
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