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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global population, with steadily increasing rates worldwide (Younossi et al, 2016, 2017; Fan et al, 2017; Stefan, 2018)
Irbesartan Suppresses Lipid Accumulation Induced by free fatty acid (FFA) and angiotensin II (AngII) in Hepatocytes
Lower lipid accumulation was seen in palmitic acid (PA)-treated cells compared to the oleic acid (OA) and FFAtreated cells, and the OA-treated L02 and Aml12 cells differed in the extent of lipid droplets
Summary
Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global population, with steadily increasing rates worldwide (Younossi et al, 2016, 2017; Fan et al, 2017; Stefan, 2018). It includes a spectrum of hepatic pathologies, including non-alcoholic fatty liver, NASH and cirrhosis, and can even lead to hepatocellular carcinoma (HCC) (Kim et al, 2017; Eslam et al, 2018). We observed significant reduction in the levels of lipids and inflammatory markers in patients with both NAFLD and hypertension following ARB treatment. The underlying mechanisms of ARB action are still unclear
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