Metformin Alleviates Steatohepatitis in Diet-Induced Obese Mice in a SIRT1-Dependent Way

Overview

Journal Front Pharmacol

Date 2021 Sep 6

PMID 34483906

Citations 13

Authors

Wan-Rong Guo

Juan Liu

Li-Dan Cheng

Zi-Yu Liu

Xiao-Bin Zheng

Hua Liang

Fen Xu

Affiliations

Soon will be listed here.

Abstract

Metformin is the first-line anti-diabetic drug for type 2 diabetes. It has been found to significantly reduce liver aminotransferase in nonalcoholic fatty liver disease (NAFLD). However, whether metformin improves NAFLD progression remains controversial. Sirtuin 1 (SIRT1), an NAD-dependent deacetylase, plays a vital role in hepatic steatosis and inflammation. Here, we investigated the effect of metformin on steatohepatitis and the role of SIRT1 in diet-induced obese (DIO) mice. The results showed that metformin significantly reduced body weight and fat mass of DIO mice. In addition, metformin also alleviated adiposity and hepatic steatosis, and greatly upregulated uncoupling protein 1 (UCP1) expression in adipose tissues of DIO mice. Unexpectedly, the effects of metformin on reducing body weight and alleviating hepatic steatosis were not impaired in heterozygous knockout ( ) mice. However, SIRT1-deficiency remarkably impaired the effects of metformin on lowering serum transaminases levels, downregulating the mRNA expression of proinflammatory factors, and increasing the protein level of hepatic Cholesterol 25-Hydroxylase (CH25H), a cholesterol hydroxylase in cholesterol catabolism. In summary, we demonstrated that metformin alleviates steatohepatitis in a SIRT1-dependent manner, and modulation of M1 polarization and cholesterol metabolism may be the underlying mechanism.

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References

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

Iogna Prat L, Tsochatzis E . The effect of antidiabetic medications on non-alcoholic fatty liver disease (NAFLD). Hormones (Athens). 2018; 17(2):219-229. DOI: 10.1007/s42000-018-0021-9. View

Sumida Y, Yoneda M . Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2017; 53(3):362-376. PMC: 5847174. DOI: 10.1007/s00535-017-1415-1. View

de Oliveira S, Houseright R, Graves A, Golenberg N, Korte B, Miskolci V . Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2018; 70(4):710-721. PMC: 6436385. DOI: 10.1016/j.jhep.2018.11.034. View

Anstee Q, Targher G, Day C . Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013; 10(6):330-44. DOI: 10.1038/nrgastro.2013.41. View

Kazankov K, Jorgensen S, Thomsen K, Moller H, Vilstrup H, George J . The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2018; 16(3):145-159. DOI: 10.1038/s41575-018-0082-x. View

Reboldi A, Dang E, McDonald J, Liang G, Russell D, Cyster J . Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science. 2014; 345(6197):679-84. PMC: 4289637. DOI: 10.1126/science.1254790. View

Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N . A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005; 100(5):1082-90. DOI: 10.1111/j.1572-0241.2005.41583.x. View

Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N . Metformin in non-alcoholic steatohepatitis. Lancet. 2001; 358(9285):893-4. DOI: 10.1016/s0140-6736(01)06042-1. View

10.

Li Y, Xu S, Mihaylova M, Zheng B, Hou X, Jiang B . AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011; 13(4):376-388. PMC: 3086578. DOI: 10.1016/j.cmet.2011.03.009. View

11.

Caton P, Nayuni N, Kieswich J, Khan N, Yaqoob M, Corder R . Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol. 2010; 205(1):97-106. DOI: 10.1677/JOE-09-0345. View

12.

Purushotham A, Schug T, Xu Q, Surapureddi S, Guo X, Li X . Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009; 9(4):327-38. PMC: 2668535. DOI: 10.1016/j.cmet.2009.02.006. View

13.

Nahrendorf M, Swirski F . Abandoning M1/M2 for a Network Model of Macrophage Function. Circ Res. 2016; 119(3):414-7. PMC: 4965179. DOI: 10.1161/CIRCRESAHA.116.309194. View

14.

Wang X, Cai B, Yang X, Sonubi O, Zheng Z, Ramakrishnan R . Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metab. 2020; 31(5):969-986.e7. PMC: 7313619. DOI: 10.1016/j.cmet.2020.03.010. View

15.

Arguello G, Balboa E, Arrese M, Zanlungo S . Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta. 2015; 1852(9):1765-78. DOI: 10.1016/j.bbadis.2015.05.015. View

16.

Wang S, Wang C, Turdi S, Richmond K, Zhang Y, Ren J . ALDH2 protects against high fat diet-induced obesity cardiomyopathy and defective autophagy: role of CaM kinase II, histone H3K9 methyltransferase SUV39H, Sirt1, and PGC-1α deacetylation. Int J Obes (Lond). 2018; 42(5):1073-1087. DOI: 10.1038/s41366-018-0030-4. View

17.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

18.

Baskaran P, Krishnan V, Ren J, Thyagarajan B . Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol. 2016; 173(15):2369-89. PMC: 4945767. DOI: 10.1111/bph.13514. View

19.

Younossi Z, Tacke F, Arrese M, Sharma B, Mostafa I, Bugianesi E . Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology. 2018; 69(6):2672-2682. DOI: 10.1002/hep.30251. View

20.

Chen J, Deng X, Liu Y, Tan Q, Huang G, Che Q . Kupffer Cells in Non-alcoholic Fatty Liver Disease: Friend or Foe?. Int J Biol Sci. 2020; 16(13):2367-2378. PMC: 7378652. DOI: 10.7150/ijbs.47143. View