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Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review)

  • Authors:
    • Yongchun Liang
    • Xinbiao Fan
    • Xiaofei Geng
    • Yunfeng Jia
    • Wenyu Shang
    • Xitong Sun
    • Jun Ge
    • Guijun Ye
    • Boyu Zhu
    • Zheng Zhang
    • Yuxin Kang
    • Xiaoyu Shan
    • Junping Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, P.R. China, Department of Cardiology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330200, P.R. China, College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
    Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 82
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    Published online on: February 3, 2026
       https://doi.org/10.3892/ijmm.2026.5753
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Abstract

Diabetic cardiomyopathy (DCM) is a significant complication in patients with diabetes, but its pathogenesis is not fully understood. In recent years, dynamic regulation of lipid droplets (LDs) balance has gradually become a new therapeutic direction with great potential. LDs regulate lipid storage, energy supply and interconnected drivers; for instance, oxidative damage, inflammation, autophagy, ferroptosis, affect the function and cellular homeostasis of cardiomyocytes, macrophages and fibroblasts, and thus participate in DCM. The present review discusses the multiple functions of LDs in regulating DCM by affecting cell homeostasis and summarizes the research progress of therapies targeting LDs and related metabolic pathways, which may inform novel strategies for preventing and treating DCM.
View Figures

Figure 1

1. Originating from the ER, lipid
droplet formation involves a four-step procedure: It starts with
nucleation, followed by growth and budding, and culminates in the
creation of an independent organelle. 2. ① DGAT aggregates neutral
lipids and completes the nucleation process. ② TAG and CEs reached
a certain concentration during the growth process to form oily
lens. ③ After being coated by phospholipids in the ER monolayer, LD
separated from ER and entered the cytoplasm. ④ The assembly of
surface proteins formed structurally and functionally complete
organelles. The process of LD decomposition includes lipophagy and
lipolysis: (A) In lipolysis, three intracellular lipases, ATGL, HSL
and MGL, hydrolyze TAG to CEs and FAs. (B) In chaperone-mediated
autophagy, intracellular HSC70 recognizes specific sequences such
as Plin2 to translocate LD into lysosomes for degradation. (C)
Macrolipophagy. LC3 binds to the PE of LD to form autophagosomes
that phagocytose LD and transport it to lysosomes. In addition, the
lipid transporter ORP8 anchors to the LD surface and interacts with
LC3 to promote the binding of LD to autophagosomes. (D) There are
relatively few studies on the mechanism of micro-lipophagy. Besides
the binding of Rab7 and Rab-interacting lysosome protein to promote
the occurrence of micro-lipophagy, GTP can also change the
structure of amphipathic helices and promote the attachment of the
complex formed by ARL8B to the LD membrane and lysosomal membrane.
ER, endoplasmic reticulum; DGAT, diacylglycerol acyltransferase;
TAG, triacylglycerol; CEs, cholesterol esters; LDs, lipid droplets;
MAG, monoacylglycerol; MGL, MAG lipase; FAs, fatty acids; HSC70,
heat shock cognate protein 70; HSL, hormone-sensitive lipase;
LAMP2A, lysosome-associated membrane protein 2A.

Figure 2

LDs and cellular metabolic
homeostasis in cardiomyocytes. ① Metabolic pathways of glucose,
BCAA and FA. ② BCAA regulates autophagy through the mTORC1/ATG/ULK1
pathway and jointly regulates SREBP with AMPK. Additionally, AMPK
inhibits HSL and promotes lipolysis regulated by ATGL. In CMA,
HSC70 recognizes and consumes Plin2. The degradation of LDs is
initiated when its KFERQ motif is recognized by HSC70 and LAMP2A on
the lysosomal surface, leading to complex formation. Under normal
circumstances, the phosphorylation of TFEB in cardiomyocytes
promotes macrolipophagy. ③ The flow of Ca2+ in
mitochondria and endoplasmic reticulum depends on the
VDAC1-GPR75-IP3R complex. ④ DGAT1/2 to facilitate the conversion of
DAG into TAG, which is stored in LDs. Moreover, excess Acyl-CoA is
also converted to TAG to protect cells from lipotoxic damage. TAG
generates DAG through ATGL and CGI58, and finally lipolysis to CE
and FA. The FA released in this process enters the mitochondria for
FAO, and lipolysis inhibits ROS production. ATGL inhibits the
accumulation of intracellular ceramides. There are membrane contact
sites such as DGAT2, Plin2 and MIGA at the contact interface
between LD and ER to regulate lipid metabolism. ⑤ Seipin and DGAT2
promote the biogenesis of LD. ⑥ The cell nucleus drives the
transcription of lipolysis-related genes (for example, SIRT1,
Plin5, PPARα and PGC-1α), along with genes such as TFEB, FOXO, and
PPARβ/γ. Maintain normal levels of FA uptake, FAO and lipid
storage. LDs, lipid droplets; BCAA, branched-chain amino acid; ATG,
autophagy-related protein; ULK1, Unc-51 like autophagy activating
kinase 1; SREBP, sterol regulatory element binding protein; HSL,
hormone-sensitive lipase; HSC70, heat shock cognate protein 70;
LAMP2A, lysosome-associated membrane protein 2A; TFEB,
transcription factor EB; ROS, reactive oxygen species; DGAT,
diacylglycerol acyltransferase; ATGL, adipose triglyceride lipase;
PPAR, peroxisome proliferator-activated receptor; FA, fatty acid;
ACSL, acyl-CoA synthetase long chain family member; CMA,
chaperone-mediated autophagy; VDAC, voltage-dependent anion
channel; GRP75, glucose-regulated protein 75; DAG, diacylglycerol;
mTORC1, mammalian target of rapamycin complex 1.

Figure 3

LDs and imbalance of cellular
metabolic homeostasis in cardiomyocytes. ① In insulin resistance,
the lipolysis of adipose tissue is enhanced, increasing the
concentration of FAs. Cardiomyocytes upregulate the expression of
receptors such as CD36, increasing the rate of FA uptake. Along
with the reduction of glucose uptake by cells through GLUT1/4, the
concentration of BCAA increases, and the effect of AMPD3 on BCKDH
is enhanced. ② Decreased FOXO and increased BCAA reduced the level
of autophagy through the mTORC1/ATG/ULK1 pathway, and FOXO and
mTORC1 reduced TFEB and its regulated macrolipophagy;
Glucolipotoxicity damaged heat shock cognate protein 70 and LAMP2A,
and inhibited CMA. When FOXO was decreased, Rab7 enhanced
mitochondrial Ca2+ overload through Rilp. ③ Similar to
the liver, in diabetic hearts the effect of IP3R-Grp75-VDAC complex
may be weakened, which reduced Ca2+ transport to the ER,
aggravated FA accumulation, and mitochondrial dysfunction. ④ ER
stress and mitochondrial dysfunction lead to massive ROS
production, which increase the expression of Pin5, ABHD5 and HSL.
Enhanced lipolysis and increased expression of DGAT1 and DGAT2
accelerate the turnover of TAG and DAG within cells. In the
meantime, FA-CoA cannot be converted to AcCoA, and with the
increase of ceramide DAG, also aggravated the lipolysis to a
certain extent. ⑤ Lipid overload activates reticulon 3-FABP5 to
regulate FA transport and increase LD biosynthesis. IP3R-Grp75-VDAC
complex increases LD production through Seipin in the liver, but it
is not clear in the heart. Insulin inhibits AMPK and mTORC-mediated
lipid degradation through the IGF1 pathway to promote LD
biosynthesis. LDs, lipid droplets; FAs, fatty acids; BCAA,
branched-chain amino acid; mTORC1, mammalian target of rapamycin
complex 1; ATG, autophagy-related protein; ULK1, Unc-51 like
autophagy activating kinase 1; TFEB, transcription factor EB;
LAMP2A, lysosome-associated membrane protein 2A; CMA,
chaperone-mediated autophagy; VDAC, voltage-dependent anion
channel; GRP75, glucose-regulated protein 75; ER, endoplasmic
reticulum; HSL, hormone-sensitive lipase; DGAT, diacylglycerol
acyltransferase; ATGL, adipose triglyceride lipase; TAG,
triacylglycerol; DAG, diacylglycerol; MGL, monoacylglycerol lipase;
Rilp, Rab-interacting lysosome protein.

Figure 4

LDs in macrophages. ① The recruitment
of lipohagy factors such as UBE2G2 and AUP1 activates LC3 and
Sequestosome 1-mediated autophagy, promoting the foaming process of
macrophages. ② AGEs promote M1 polarization through the
mir-471-3p/SIRT1 pathway, generating a large amount of ROS and NO.
The long-term maintenance of the M2 phenotype depends on PPARγ.
M2-type macrophages exhibit low levels of glycolysis and high
levels of oxidative phosphorylation, as well as more LD
accumulation. TGFβ can reduce LD accumulation. Multiple pathogens
promote the foaming of macrophages. Mtb enables macrophages to
switch from the glycolysis pathway to ketone body synthesis. It
also regulates the cGAS/STING pathway to accelerate the formation
of foam cells, and pneumococcus accelerates the foaming process
through ROS. ③ Before lipolysis, Plin2 on the LD surface was
recognized by heat shock cognate protein 70 at the KFERQ motif and
degraded by lysosomes after interacting with LAMP2A. ④ ABHD5 and
ATGL promote the conversion of TAG to DAG, and continue to
hydrolyze CE and FA through MGL, and HSL continue to hydrolyze CE
to free cholesterol and FA, and FA enters mitochondria for FAO.
FOXC2/Angptl2 promotes LD accumulation. ⑤ The regulation process of
TAG and CE levels in macrophages. GPAT3 and GPAT4 help FA
synthesize TAG, CES1 and ATGL hydrolyze CE to FA, and HILDPA
inhibits ATGL-regulated lipolysis. It catalyzes the synthesis of
cholesterol to CE at ACAT, which is then decomposed to cholesterol
by neutral cholesterol ester hydrolase 1 (NECH1). ABCA1 and ABCG1
contribute to cholesterol efflux when excess cholesterol
accumulates. LDs, lipid droplets; AGEs, advanced glycation end
products; ROS, reactive oxygen species; NO, nitric oxide; PPAR,
peroxisome proliferator-activated receptor; ATGL, adipose
triglyceride lipase; LAMP2A, lysosome-associated membrane protein
2A; TAG, triacylglycerol; DAG, diacylglycerol; HSL,
hormone-sensitive lipase; CMA, chaperone-mediated autophagy; oxLDL,
oxidized low-density lipoprotein; FA, fatty acid; FFA, free FA;
DHA, docosahexaenoic acid; HDL, high-density lipoprotein.

Figure 5

Multiple functions of LDs. (A)
Excessive glucose stimulation of ABHD5 inhibits MEF2-triggered
hexosamine synthesis pathway and Stim1 protein expression through
HDAC4 to protect the heart. During glucose deprivation, PFKL
enhances the binding of Plin2 to CPT1A to promote FAO and
lipolysis. (B) BCAA and FGF21 achieve the metabolic link between
heart and liver. When cardiac BCAA metabolism is impaired, BCKDH is
decreased and AMPD3 is increased, resulting in increased LD
biosynthesis and decreased FAO rate. (C) Difference in lipotoxic
damage caused by the formation of LD by saturated fatty acids and
unsaturated fatty acids. (D) LD affects macrophage polarization,
foam cell formation, and accelerates the formation of
atherosclerotic plaques. (E) Plin5 promotes PDM to enhance FAO. (F)
Downregulation of ABHD5 leads to blocked lipolysis and increased LD
accumulation, which is caused by abnormal LD biosynthesis and
increased accumulation of unfolded protein inducing ER stress. By
upregulating EDEM2, XBP1s promotes the SEC23A-dependent
translocation of ATGL and prevents its degradation, thereby
alleviating myocardial lipotoxicity. (G) LD regulates normal cell
division, autophagy, and ferroptosis. LD accumulation increased in
the cell cycle arrest state, and G0S2 inhibited ATGL-regulated
lipolysis. Impairment of FSP1 significantly induces peroxidation of
PUFA-LDs leading to ferroptosis of cardiomyocytes. Rab7 and Rilp
mediate macrolipophagy of LD. LDs, lipid droplets; HDAC4, histone
deacetylase 4; PFKL, phosphofructokinase, liver type; FAO, fatty
acid oxidation; BCAA, branched-chain amino acid; ER, endoplasmic
reticulum; ROS, reactive oxygen species; TG, triglyceride; NLRP3,
NLRP3, NOD-like receptor thermal protein domain associated protein
3; ATGL, adipose triglyceride lipase; PUFA, polyunsaturated fatty
acid-rich; XBP1, X-box binding protein 1; Rilp, Rab-interacting
lysosome protein; Mfn2, mitofusin 2; Coq10, coenzyme Q10; PPAR,
peroxisome proliferator-activated receptor; G0S2, G0/G1 switch 2
gene.
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Copy and paste a formatted citation
Spandidos Publications style
Liang Y, Fan X, Geng X, Jia Y, Shang W, Sun X, Ge J, Ye G, Zhu B, Zhang Z, Zhang Z, et al: Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review). Int J Mol Med 57: 82, 2026.
APA
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X. ... Zhang, J. (2026). Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review). International Journal of Molecular Medicine, 57, 82. https://doi.org/10.3892/ijmm.2026.5753
MLA
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X., Ge, J., Ye, G., Zhu, B., Zhang, Z., Kang, Y., Shan, X., Zhang, J."Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review)". International Journal of Molecular Medicine 57.4 (2026): 82.
Chicago
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X., Ge, J., Ye, G., Zhu, B., Zhang, Z., Kang, Y., Shan, X., Zhang, J."Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 82. https://doi.org/10.3892/ijmm.2026.5753
Copy and paste a formatted citation
x
Spandidos Publications style
Liang Y, Fan X, Geng X, Jia Y, Shang W, Sun X, Ge J, Ye G, Zhu B, Zhang Z, Zhang Z, et al: Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review). Int J Mol Med 57: 82, 2026.
APA
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X. ... Zhang, J. (2026). Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review). International Journal of Molecular Medicine, 57, 82. https://doi.org/10.3892/ijmm.2026.5753
MLA
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X., Ge, J., Ye, G., Zhu, B., Zhang, Z., Kang, Y., Shan, X., Zhang, J."Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review)". International Journal of Molecular Medicine 57.4 (2026): 82.
Chicago
Liang, Y., Fan, X., Geng, X., Jia, Y., Shang, W., Sun, X., Ge, J., Ye, G., Zhu, B., Zhang, Z., Kang, Y., Shan, X., Zhang, J."Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 82. https://doi.org/10.3892/ijmm.2026.5753
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