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

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 in vitro 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.

Isoschaftoside Reverses Nonalcoholic Fatty Liver Disease via Activating Autophagy In Vivo and In Vitro

“…In the Oil Red O staining, compared with the control group, lipid deposition was significantly increased in the CQ group, indicating that CQ inhibited the autophagy flux of HepG2 cells, leading to lipid deposition ( Figure 2(b) , control group vs CQ group). In general, the inhibition of autophagy flux can lead to lipid deposition [ 30 , 31 ], and the activation of autophagy flux can reduce lipid deposition, which also provides a theoretical basis for our experiment.…”

Mesenchymal stem cells promote chemoresistance by activating autophagy in intrahepatic cholangiocarcinoma

“…The present study then investigated the mechanism underlying IL-6-mediated autophagy activation. Previous studies have reported that the AMPK/mTOR signaling pathway mediates cell autophagy activation ( 33 , 34 ), and that activated AMPK negatively regulated mTOR and thereby enhanced autophagy flux. Therefore, phosphorylated (p)-AMPK, AMPK, p-mTOR and mTOR levels were detected in cholangiocarcinoma cells following IL-6 treatment using western blotting in the present study.…”

“…The present study then investigated the mechanism underlying IL-6-mediated autophagy activation. Previous studies have reported that the AMPK/mTOR signaling pathway mediates cell autophagy activation (33,34), and that activated AMPK negatively regulated mTOR and Table I. Baseline characteristics of patients.…”

Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed

“…Recently, irbesartan was reported to inhibit the mitochondrial apoptotic pathway by reducing the expression of the Bax, tBid, active caspase-9 and -3, and therefore to attenuate sleep apnea-induced cardiac apoptosis [ 62 ]. In an in vitro model of non-alcoholic fatty liver disease consisting of free fatty acid-treated hepatocytes, irbesartan attenuated lipid deposition and mitochondrial dysfunction by increasing ATP production and the mitochondrial membrane potential, and by lowering ROS production [ 63 ]. Moreover, the authors found that irbesartan enhanced autophagy via the PKC/AMPK/ULK1 axis [ 63 ].…”