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.