Irbesartan Ameliorates Lipid Deposition by Enhancing Autophagy Via PKC/AMPK/ULK1 Axis in Free Fatty Acid Induced Hepatocytes

Overview

Journal Front Physiol

Date 2019 Jun 14

PMID 31191364

Citations 8

Authors

Juan He

Jian Ding

Qiuhua Lai

Xinke Wang

Aimin Li

Side Liu

Affiliations

Soon will be listed here.

Abstract

Irbesartan has shown significant therapeutic effects in hypertensive patients with non-alcoholic fatty liver disease (NAFLD). To determine the underlying mechanisms of its action, we established an model of NAFLD by treating human and mouse hepatocytes with free fatty acids (FFAs) and angiotensin (Ang) II. Irbesartan significantly reversed AngII/FFA-induced lipid deposition and mitochondrial dysfunction by restoring ATP production and the mitochondrial membrane potential (MMP), and decreasing the levels of reactive oxygen species (ROS) and inflammatory markers. In addition, irbesartan also increased the autophagy flux, in terms of increased numbers of autolysosomes and autophagosomes, and the upregulation and mitochondrial localization of the autophagic proteins Atg5 and LC3BII/I. Activation of protein kinase C (PKC) and inhibition of the autophagic flux exacerbated mitochondrial dysfunction in the steatotic hepatocytes. Furthermore, AngII upregulated PKC which inhibited AMPK phosphorylation via direct interaction with the AngII receptor AT1-R. Irbesartan inhibited PKC and activated AMPK and its downstream effector ULK1, thereby inducing autophagy, decreasing lipid deposition, and restoring mitochondrial function. Taken together, irbesartan triggers autophagy via the PKC/AMPK/ULK1 axis to ameliorate the pathological changes in the steatotic hepatocytes.

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References

Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T . Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001; 34(4 Pt 1):745-50. DOI: 10.1053/jhep.2001.28231. View

Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K . Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004; 40(5):1222-5. DOI: 10.1002/hep.20420. View

Yang L, Bataller R, Dulyx J, Coffman T, Gines P, Rippe R . Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005; 43(2):317-23. DOI: 10.1016/j.jhep.2005.02.034. View

Sugimoto K, Qi N, Kazdova L, Pravenec M, Ogihara T, Kurtz T . Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006; 47(5):1003-9. DOI: 10.1161/01.HYP.0000215181.60228.f7. View

Mizushima N, Levine B, Cuervo A, Klionsky D . Autophagy fights disease through cellular self-digestion. Nature. 2008; 451(7182):1069-75. PMC: 2670399. DOI: 10.1038/nature06639. View

Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H . Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int. 2009; 29(7):1078-85. DOI: 10.1111/j.1478-3231.2009.01988.x. View

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M . Autophagy regulates lipid metabolism. Nature. 2009; 458(7242):1131-5. PMC: 2676208. DOI: 10.1038/nature07976. View

Nabeshima Y, Tazuma S, Kanno K, Hyogo H, Chayama K . Deletion of angiotensin II type I receptor reduces hepatic steatosis. J Hepatol. 2009; 50(6):1226-35. DOI: 10.1016/j.jhep.2009.01.018. View

Fabbrini E, Sullivan S, Klein S . Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2009; 51(2):679-89. PMC: 3575093. DOI: 10.1002/hep.23280. View

10.

Yadav A, Vallabu S, Arora S, Tandon P, Slahan D, Teichberg S . ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol. 2010; 299(2):C488-96. PMC: 2928643. DOI: 10.1152/ajpcell.00424.2009. View

11.

Ding W, Li M, Chen X, Ni H, Lin C, Gao W . Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010; 139(5):1740-52. PMC: 4129642. DOI: 10.1053/j.gastro.2010.07.041. View

12.

Neuschwander-Tetri B . Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010; 52(2):774-88. DOI: 10.1002/hep.23719. View

13.

Rautou P, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R . Autophagy in liver diseases. J Hepatol. 2010; 53(6):1123-34. DOI: 10.1016/j.jhep.2010.07.006. View

14.

Greene M, Burrington C, Ruhoff M, Johnson A, Chongkrairatanakul T, Kangwanpornsiri A . PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death. J Biol Chem. 2010; 285(53):42115-29. PMC: 3009937. DOI: 10.1074/jbc.M110.168575. View

15.

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

16.

Sturzeneker M, Ioshii S, Baroncini L, Precoma D . Olmesartan severely weakened the development of NASH in an animal model of hypercholesterolemia. Atherosclerosis. 2011; 216(1):97-102. DOI: 10.1016/j.atherosclerosis.2011.01.047. View

17.

Cusi K . Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012; 142(4):711-725.e6. DOI: 10.1053/j.gastro.2012.02.003. View

18.

Kato J, Koda M, Kishina M, Tokunaga S, Matono T, Sugihara T . Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan, on non-alcoholic steatohepatitis using FLS-ob/ob male mice. Int J Mol Med. 2012; 30(1):107-13. DOI: 10.3892/ijmm.2012.958. View

19.

Morris E, Fletcher J, Thyfault J, Rector R . The role of angiotensin II in nonalcoholic steatohepatitis. Mol Cell Endocrinol. 2012; 378(1-2):29-40. DOI: 10.1016/j.mce.2012.04.013. View

20.

Wong P, Puente C, Ganley I, Jiang X . The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy. 2013; 9(2):124-37. PMC: 3552878. DOI: 10.4161/auto.23323. View