Role of Ca<sup>2+</sup> channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)

Chen,Xingyue; Zhang,Li; Zheng,Liming; Tuo,Biguang

doi:10.3892/ijmm.2022.5169

September-2022 Volume 50 Issue 3

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

September-2022 Volume 50 Issue 3

Full Size Image

Review Open Access

Role of Ca²⁺ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review)

Authors:
- Xingyue Chen
- Li Zhang
- Liming Zheng
- Biguang Tuo
View Affiliations / Copyright

Affiliations: Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China

Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 113
|
Published online on: July 4, 2022

https://doi.org/10.3892/ijmm.2022.5169
Expand metrics +

Abstract

Non‑alcoholic fatty liver disease (NAFLD) is a clinically progressive illness that can advance from simple fatty liver to non-alcoholic hepatitis and liver fibrosis. Cirrhosis and hepatocellular carcinoma are two of the most common diseases caused by NAFLD. As there are no early disease biomarkers and no US Food and Drug Administration‑approved medications, treatment for NAFLD is still focused on altering lifestyle and dietary habits, which makes it difficult to treat effectively. As a result, a novel treatment is urgently needed to prevent NAFLD progression. Calcium (Ca²⁺) channels regulate intracellular Ca²⁺ homeostasis via the mediation of Ca²⁺ flow. Previous studies have reported that Ca²⁺ channel expression varies throughout the development and progression of NAFLD, which results in the dysregulation of intracellular Ca²⁺ homeostasis, endoplasmic reticulum stress, mitochondrial dysfunction and autophagy suppression, all of which contribute to NAFLD progression. Several types of Ca²⁺ channels (including two‑pore segment channel 2, transient receptor potential, inositol triphosphate receptor, voltage‑dependent anion channel 1, store‑operated Ca²⁺ entry, purinergic receptor X7 and potassium Ca²⁺‑activated channel subfamily N member 4) have been identified as potential targets for preventing NAFLD development and controlling intracellular Ca²⁺ homeostasis. To achieve this, these channels can be blocked or activated, which exerts anti‑steatotic, anti‑inflammatory, anti‑fibrotic and other effects, which ultimately prevents the development of NAFLD. In the present review NAFLD therapeutics and the treatments that target Ca²⁺ channels that are currently being developed were examined.

View Figures

View References

1	Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S, Maher JJ, Bugianesi E, Sirlin CB, Neuschwander-Tetri BA and Rinella ME: Nonalcoholic fatty liver disease. Nat Rev Dis Primers. 1:150802015. View Article : Google Scholar : PubMed/NCBI
2	Gusdon AM, Song KX and Qu S: Nonalcoholic fatty liver disease: Pathogenesis and therapeutics from a mitochondria-centric perspective. Oxid Med Cell Longev. 2014:6370272014. View Article : Google Scholar : PubMed/NCBI
3	Zhu JZ, Dai YN, Wang YM, Zhou QY, Yu CH and Li YM: Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci 2015. Nov;60:3194–3202. 2015. View Article : Google Scholar
4	Neuschwander-Tetri BA: Non-alcoholic fatty liver disease. BMC Med. 15:452017. View Article : Google Scholar : PubMed/NCBI
5	Stefan N, Häring H and Cusi K: Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 7:313–324. 2019. View Article : Google Scholar
6	Manne V, Handa P and Kowdley KV: Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis. 22:23–37. 2018. View Article : Google Scholar
7	Varela-Rey M, Embade N, Ariz U, Lu SC, Mato JM and Martínez-Chantar ML: Non-alcoholic steatohepatitis and animal models: Understanding the human disease. Int J Biochem Cell Biol. 41:969–976. 2009. View Article : Google Scholar
8	Day CP and James OF: Steatohepatitis: A tale of two 'hits'? Gastroenterology. 114:842–845. 1998. View Article : Google Scholar : PubMed/NCBI
9	Friedman SL, Neuschwander-Tetri BA, Rinella M and Sanyal AJ: Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 24:908–922. 2018. View Article : Google Scholar : PubMed/NCBI
10	Buzzetti E, Pinzani M and Tsochatzis E: The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 65:1038–1048. 2016. View Article : Google Scholar : PubMed/NCBI
11	Schuppan D and Schattenberg JM: Non-alcoholic steatohepatitis: Pathogenesis and novel therapeutic approaches. J Gastroenterol Hepatol. 28(Suppl 1): S68–S76. 2013. View Article : Google Scholar
12	Cortez-Pinto H, de Moura MC and Day CP: Non-alcoholic steatohepatitis: From cell biology to clinical practice. J Hepatol. 44:197–208. 2006. View Article : Google Scholar
13	Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, Racila A, Hunt S and Beckerman R: The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 64:1577–1586. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM and Ahmed A: Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 148:547–555. 2015. View Article : Google Scholar
15	Kiselyov K and Muallem S: ROS and intracellular ion channels. Cell Calcium. 60:108–114. 2016. View Article : Google Scholar : PubMed/NCBI
16	Guéguinou M, Chantôme A, Fromont G, Bougnoux P, Vandier C and Potier-Cartereau M: KCa and Ca(2+) channels: The complex thought. Biochim Biophys Acta. 1843:2322–2333. 2014. View Article : Google Scholar : PubMed/NCBI
17	Ramírez A, Vázquez-Sánchez AY, Carrión-Robalino N and Camacho J: Ion channels and oxidative stress as a potential link for the diagnosis or treatment of liver diseases. Oxid Med Cell Longev. 2016:39287142016. View Article : Google Scholar : PubMed/NCBI
18	Ali ES, Rychkov GY and Barritt GJ: Targeting Ca²⁺ signaling in the initiation, promotion and progression of hepatocellular carcinoma. Cancers (Basel). 12:27552020. View Article : Google Scholar
19	Ben-Moshe S and Itzkovitz S: Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol. 16:395–410. 2019. View Article : Google Scholar : PubMed/NCBI
20	Garcin I and Tordjmann T: Calcium signalling and liver regeneration. Int J Hepatol. 2012:6306702012. View Article : Google Scholar : PubMed/NCBI
21	Taira Z, Ueda Y, Monmasu H, Yamase D, Miyake S and Shiraishi M: Characteristics of intracellular Ca²⁺ signals consisting of two successive peaks in hepatocytes during liver regeneration after 70% partial hepatectomy in rats. J Exp Pharmacol. 8:21–33. 2016. View Article : Google Scholar :
22	Berridge MJ, Bootman MD and Roderick HL: Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 4:517–529. 2003. View Article : Google Scholar : PubMed/NCBI
23	Wu L, Lian W and Zhao L: Calcium signaling in cancer progression and therapy. FEBS J. 288:6187–6205. 2021. View Article : Google Scholar : PubMed/NCBI
24	Oliva-Vilarnau N, Hankeova S, Vorrink SU, Mkrtchian S, Andersson ER and Lauschke VM: Calcium signaling in liver injury and regeneration. Front Med (Lausanne). 5:1922018. View Article : Google Scholar
25	Bartlett P, Gaspers L, Pierobon N and Thomas A: Calcium-dependent regulation of glucose homeostasis in the liver. Cell Calcium. 55:306–316. 2014. View Article : Google Scholar : PubMed/NCBI
26	Chen CC, Hsu LW, Chen KD, Chiu KW, Chen CL and Huang KT: Emerging roles of calcium signaling in the development of non-alcoholic fatty liver disease. Int J Mol Sci. 23:2562021. View Article : Google Scholar
27	Wang J, He W, Tsai PJ, Chen PH, Ye M, Guo J and Su Z: Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease. Lipids Health Dis. 19:722020. View Article : Google Scholar : PubMed/NCBI
28	Arruda A, Pers B, Parlakgul G, Güney E, Goh T, Cagampan E, Lee GY, Goncalves RL and Hotamisligil GS: Defective STIM-mediated store operated Ca²⁺ entry in hepatocytes leads to metabolic dysfunction in obesity. Elife. 6:e299682017. View Article : Google Scholar
29	Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA and Cahalan MD: STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature. 437:902–905. 2005. View Article : Google Scholar : PubMed/NCBI
30	Park SW, Zhou Y, Lee J, Lee J and Ozcan U: Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci USA. 107:19320–19325. 2010. View Article : Google Scholar : PubMed/NCBI
31	Egnatchik RA, Leamy AK, Jacobson DA, Shiota M and Young JD: ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol Metab. 3:544–553. 2014. View Article : Google Scholar : PubMed/NCBI
32	Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR and Hotamisligil GS: Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 473:528–531. 2011. View Article : Google Scholar : PubMed/NCBI
33	Amaya M and Nathanson M: Calcium signaling in the liver. Compr Physiol. 3:515–539. 2013. View Article : Google Scholar : PubMed/NCBI
34	Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T and Rizzuto R: Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol. 175:901–911. 2006. View Article : Google Scholar : PubMed/NCBI
35	Masarone M, Rosato V, Dallio M, Gravina AG, Aglitti A, Loguercio C, Federico A and Persico M: Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2018:95476132018. View Article : Google Scholar : PubMed/NCBI
36	Luzio JP, Hackmann Y, Dieckmann NM and Griffiths GM: The biogenesis of lysosomes and lysosome-related organelles. Cold Spring Harb Perspect Biol. 6:a0168402014. View Article : Google Scholar : PubMed/NCBI
37	Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM and Czaja MJ: Autophagy regulates lipid metabolism. Nature. 458:1131–1135. 2009. View Article : Google Scholar : PubMed/NCBI
38	Lin CW, Zhang H, Li M, Xiong X, Chen X, Chen X, Dong XC and Yin XM: Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol. 58:993–999. 2013. View Article : Google Scholar : PubMed/NCBI
39	Ali ES, Rychkov GY and Barritt GJ: Deranged hepatocyte intracellular Ca²⁺ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma. Cell Calcium. 82:1020572019. View Article : Google Scholar
40	Miyagawa K, Oe S, Honma Y, Izumi H, Baba R and Harada M: Lipid-induced endoplasmic reticulum stress impairs selective autophagy at the step of autophagosome-lysosome fusion in hepatocytes. Am J Pathol. 186:1861–1873. 2016. View Article : Google Scholar : PubMed/NCBI
41	Koo JH and Han CY: Signaling nodes associated with endoplasmic reticulum stress during NAFLD progression. Biomolecules. 11:2422021. View Article : Google Scholar : PubMed/NCBI
42	Ali ES and Petrovsky N: Calcium signaling as a therapeutic target for liver steatosis. Trends Endocrinol Metab. 30:270–281. 2019. View Article : Google Scholar : PubMed/NCBI
43	Grimm C, Holdt LM, Chen CC, Hassan S, Müller C, Jörs S, Cuny H, Kissing S, Schröder B, Butz E, et al: High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nat Commun. 5:46992014. View Article : Google Scholar : PubMed/NCBI
44	Li Q, Li L, Wang F, Chen J, Zhao Y, Wang P, Nilius B, Liu D and Zhu Z: Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activate receptor delta activation. Pflugers Arch. 465:1303–1316. 2013. View Article : Google Scholar : PubMed/NCBI
45	Li L, Chen J, Ni Y, Feng X, Zhao Z, Wang P, Sun J, Yu H, Yan Z, Liu D, et al: TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflugers Arch. 463:727–732. 2012. View Article : Google Scholar : PubMed/NCBI
46	Wang K, Tan W, Liu X, Deng L, Huang L, Wang X and Gao X: New insight and potential therapy for NAFLD: CYP2E1 and flavonoids. Biomed Pharmacother. 137:1113262021. View Article : Google Scholar : PubMed/NCBI
47	Seth RK, Das S, Dattaroy D, Chandrashekaran V, Alhasson F, Michelotti G, Nagarkatti M, Nagarkatti P, Diehl AM, Bell PD, et al: TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med. 102:260–273. 2017. View Article : Google Scholar
48	Feng Q, Liu C, Gao W, Geng XL and Dai N: Salidroside-mitigated inflammatory injury of hepatocytes with non-alcoholic fatty liver disease via inhibition TRPM2 ion channel activation. Diabetes Metab Syndr Obes. 12:2755–2763. 2019. View Article : Google Scholar
49	Ali ES, Rychkov GY and Barritt GJ: TRPM2 non-selective cation channels in liver injury mediated by reactive oxygen species. Antioxidants (Basel). 10:12432021. View Article : Google Scholar
50	Yu T, Zheng E, Li Y, Li Y, Xia J, Ding Q, Hou Z, Ruan XZ, Zhao L and Chen Y: Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes. Exp Cell Res. 399:1124382021. View Article : Google Scholar
51	Feriod CN, Oliveira AG, Guerra MT, Nguyen L, Richards KM, Jurczak MJ, Ruan HB, Camporez JP, Yang X, Shulman GI, et al: Hepatic inositol 1,4,5 trisphosphate receptor type 1 mediates fatty liver. Hepatol Commun. 1:23–35. 2017. View Article : Google Scholar : PubMed/NCBI
52	Khamphaya T, Chukijrungroat N, Saengsirisuwan V, Mitchell-Richards KA, Robert ME, Mennone A, Ananthanarayanan M, Nathanson MH and Weerachayaphorn J: Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor. Hepatology. 67:560–574. 2018. View Article : Google Scholar
53	Smedlund K, Dube P and Vazquez G: Early steatohepatitis in hyperlipidemic mice with endothelial-specific gain of TRPC3 function precedes changes in aortic atherosclerosis. Physiol Genomics. 48:644–649. 2016. View Article : Google Scholar : PubMed/NCBI
54	Zhu Y, Zhang C, Xu F, Zhao M, Bergquist J, Yang C, Liu X, Tan Y, Wang X, Li S, et al: System biology analysis reveals the role of voltage-dependent anion channel in mitochondrial dysfunction during non-alcoholic fatty liver disease progression into hepatocellular carcinoma. Cancer Sci. 111:4288–4302. 2020. View Article : Google Scholar : PubMed/NCBI
55	Ali ES, Rychkov GY and Barritt GJ: Metabolic disorders and cancer: Hepatocyte store-operated Ca²⁺ channels in nonalcoholic fatty liver disease. Adv Exp Med Biol. 993:595–621. 2017. View Article : Google Scholar
56	Wilson CH, Ali ES, Scrimgeour N, Martin AM, Hua J, Tallis GA, Rychkov GY and Barritt GJ: Steatosis inhibits liver cell store-operated Ca²⁺ entry and reduces ER Ca²⁺ through a protein kinase C-dependent mechanism. Biochem J. 466:379–390. 2015. View Article : Google Scholar
57	Zhang B, Yang W, Zou Y, Li M, Guo H, Zhang H, Xia C and Xu C: NEFA-sensitive Orai1 expression in regulation of de novo lipogenesis. Cell Physiol Biochem. 47:1310–1317. 2018. View Article : Google Scholar : PubMed/NCBI
58	Zhang B, Li M, Zou Y, Guo H, Zhang B, Xia C, Zhang H, Yang W and Xu C: NFκB/Orai1 facilitates endoplasmic reticulum stress by oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Front Cell Dev Biol. 7:2022019. View Article : Google Scholar
59	Chatterjee S, Rana R, Corbett J, Kadiiska MB, Goldstein J and Mason RP: P2X7 receptor-NADPH oxidase axis mediates protein radical formation and Kupffer cell activation in carbon tetrachloride-mediated steatohepatitis in obese mice. Free Radic Biol Med. 52:1666–1679. 2012. View Article : Google Scholar : PubMed/NCBI
60	Das S, Seth RK, Kumar A, Kadiiska MB, Michelotti G, Diehl AM and Chatterjee S: Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 305:G950–G963. 2013. View Article : Google Scholar : PubMed/NCBI
61	Freise C, Heldwein S, Erben U, Hoyer J, Köhler R, Jöhrens K, Patsenker E, Ruehl M, Seehofer D, Stickel F and Somasundaram R: K⁺-channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int. 35:1244–1252. 2015. View Article : Google Scholar
62	Paka L, Smith DE, Jung D, McCormack S, Zhou P, Duan B, Li JS, Shi J, Hao YJ, Jiang K, et al: Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, senicapoc, in non-alcoholic liver disease. World J Gastroenterol. 23:4181–4190. 2017. View Article : Google Scholar : PubMed/NCBI
63	Morgan AJ and Galione A: Two-pore channels (TPCs): Current controversies. Bioessays. 36:173–183. 2014. View Article : Google Scholar
64	Patel S and Kilpatrick BS: Two-pore channels and disease. Biochim Biophys Acta Mol Cell Res. 1865:1678–1686. 2018. View Article : Google Scholar : PubMed/NCBI
65	Bishnoi M, Khare P, Brown L and Panchal SK: Transient receptor potential (TRP) channels: A metabolic TR(i)P to obesity prevention and therapy. Obes Rev. 19:1269–1292. 2018. View Article : Google Scholar : PubMed/NCBI
66	Zhu Z, Luo Z, Ma S and Liu D: TRP channels and their implications in metabolic diseases. Pflugers Arch. 461:211–223. 2011. View Article : Google Scholar
67	Nilius B and Owsianik G: The transient receptor potential family of ion channels. Genome Biol. 12:2182011. View Article : Google Scholar : PubMed/NCBI
68	Venkatachalam K and Montell C: TRP channels. Annu Rev Biochem. 76:387–417. 2007. View Article : Google Scholar : PubMed/NCBI
69	Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, et al: Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 100:1063–1070. 2007. View Article : Google Scholar : PubMed/NCBI
70	Uchida K, Dezaki K, Yoneshiro T, Watanabe T, Yamazaki J, Saito M, Yada T, Tominaga M and Iwasaki Y: Involvement of thermosensitive TRP channels in energy metabolism. J Physiol Sci. 67:549–560. 2017. View Article : Google Scholar : PubMed/NCBI
71	Park HW and Lee JH: Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy. 10:2385–2386. 2014. View Article : Google Scholar : PubMed/NCBI
72	Polyzos SA, Kountouras J and Mantzoros CS: Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism. 92:82–97. 2019. View Article : Google Scholar
73	Li J, Li X, Liu D, Zhang S, Tan N, Yokota H and Zhang P: Phosphorylation of eIF2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner. Cell Death Dis. 11:10692020. View Article : Google Scholar
74	Baffy G: Uncoupling protein-2 and non-alcoholic fatty liver disease. Front Biosci. 10:2082–2096. 2005. View Article : Google Scholar : PubMed/NCBI
75	Panchal SK, Bliss E and Brown L: Capsaicin in metabolic syndrome. Nutrients. 10:6302018. View Article : Google Scholar :
76	Yang L, Li P, Fu S, Calay E and Hotamisligil GS: Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11:467–478. 2010. View Article : Google Scholar : PubMed/NCBI
77	Everaerts W, Nilius B and Owsianik G: The vanilloid transient receptor potential channel TRPV4: From structure to disease. Prog Biophys Mol Biol. 103:2–17. 2010. View Article : Google Scholar
78	Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, et al: TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 151:96–110. 2012. View Article : Google Scholar : PubMed/NCBI
79	Zhan L, Yang Y, Ma TT, Huang C, Meng XM, Zhang L and Li J: Transient receptor potential vanilloid 4 inhibits rat HSC-T6 apoptosis through induction of autophagy. Mol Cell Biochem. 402:9–22. 2015. View Article : Google Scholar : PubMed/NCBI
80	Song Y, Zhan L, Yu M, Huang C, Meng X, Ma T, Zhang L and Li J: TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells. PLoS One. 9:e1011792014. View Article : Google Scholar
81	Fonfria E, Murdock PR, Cusdin FS, Benham CD, Kelsell RE and McNulty S: Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res. 26:159–178. 2006. View Article : Google Scholar : PubMed/NCBI
82	Kheradpezhouh E, Ma L, Morphett A, Barritt GJ and Rychkov GY: TRPM2 channels mediate acetaminophen-induced liver damage. Proc Natl Acad Sci USA. 111:3176–3181. 2014. View Article : Google Scholar : PubMed/NCBI
83	Vanderheyden V, Devogelaere B, Missiaen L, De Smedt H, Bultynck G and Parys JB: Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta. 1793:959–970. 2009. View Article : Google Scholar : PubMed/NCBI
84	Arruda AP, Pers BM, Parlakgül G, Güney E, Inouye K and Hotamisligil GS: Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med. 20:1427–1435. 2014. View Article : Google Scholar : PubMed/NCBI
85	Rodrigues MA, Gomes DA, Leite MF, Grant W, Zhang L, Lam W, Cheng YC, Bennett AM and Nathanson MH: Nucleoplasmic calcium is required for cell proliferation. J Biol Chem. 282:17061–17068. 2007. View Article : Google Scholar : PubMed/NCBI
86	Lemasters JJ and Holmuhamedov E: Voltage-dependent anion channel (VDAC) as mitochondrial governator-thinking outside the box. Biochim Biophys Acta. 1762:181–190. 2006. View Article : Google Scholar
87	Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N and Arbel N: VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med. 31:227–285. 2010. View Article : Google Scholar : PubMed/NCBI
88	Pittala S, Krelin Y, Kuperman Y and Shoshan-Barmatz V: A mitochondrial VDAC1-based peptide greatly suppresses steatosis and NASH-associated pathologies in a mouse model. Mol Ther. 27:1848–1862. 2019. View Article : Google Scholar : PubMed/NCBI
89	Prakriya M and Lewis RS: Store-operated calcium channels. Physiol Rev. 95:1383–1436. 2015. View Article : Google Scholar : PubMed/NCBI
90	Kappel S, Borgström A, Stoklosa P, Dörr K and Peinelt C: Store-operated calcium entry in disease: Beyond STIM/Orai expression levels. Semin Cell Dev Biol. 94:66–73. 2019. View Article : Google Scholar : PubMed/NCBI
91	Li Y, Ge M, Ciani L, Kuriakose G, Westover EJ, Dura M, Covey DF, Freed JH, Maxfield FR, Lytton J and Tabas I: Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: Implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem. 279:37030–37039. 2004. View Article : Google Scholar : PubMed/NCBI
92	Maus M, Cuk M, Patel B, Lian J, Ouimet M, Kaufmann U, Yang J, Horvath R, Hornig-Do HT, Chrzanowska-Lightowlers ZM, et al: Store-operated Ca²⁺ entry controls induction of lipolysis and the transcriptional reprogramming to lipid metabolism. Cell Metab. 25:698–712. 2017. View Article : Google Scholar : PubMed/NCBI
93	Jain S and Jacobson KA: Purinergic signaling in liver pathophysiology. Front Endocrinol (Lausanne). 12:7184292021. View Article : Google Scholar
94	Jiang M, Cui BW, Wu YL, Zhang Y, Shang Y, Liu J, Yang HX, Qiao CY, Zhan ZY, Ye H, et al: P2X7R orchestrates the progression of murine hepatic fibrosis by making a feedback loop from macrophage to hepatic stellate cells. Toxicol Lett. 333:22–32. 2020. View Article : Google Scholar : PubMed/NCBI
95	Takenouchi T, Nakai M, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Wei J, Sekigawa A, Sato M, Kojima S, et al: The activation of P2X7 receptor impairs lysosomal functions and stimulates the release of autophagolysosomes in microglial cells. J Immunol. 182:2051–2062. 2009. View Article : Google Scholar : PubMed/NCBI
96	Chatterjee S and Das S: P2X7 receptor as a key player in oxidative stress-driven cell fate in nonalcoholic steatohepatitis. Oxid Med Cell Longev. 2015:1724932015. View Article : Google Scholar : PubMed/NCBI
97	Wulff H and Castle NA: Therapeutic potential of KCa3.1 blockers: Recent advances and promising trends. Expert Rev Clin Pharmacol. 3:385–396. 2010. View Article : Google Scholar : PubMed/NCBI
98	Alkhouri N, Dixon LJ and Feldstein AE: Lipotoxicity in nonalcoholic fatty liver disease: Not all lipids are created equal. Expert Rev Gastroenterol Hepatol. 3:445–451. 2009. View Article : Google Scholar : PubMed/NCBI

Journals