AMP-activated protein kinase regulates lipid metabolism and the fibrotic phenotype of hepatic stellate cells through inhibition of autophagy

Hepatic stellate cells (HSCs) are the principal hepatic cell type responsible for liver fibrosis. Although AMP-activated protein kinase (AMPK) is known to regulate the activation of HSCs, little is known about its underlying molecular mechanisms. In the present study, we demonstrate that AMPK activation by 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR) restricts the fibrotic potential elicited by transforming growth factor beta (TGF-beta) in LX-2 cells through modulation of autophagy. AICAR treatment activated the mechanistic target of rapamycin/Akt pathway and thus inhibited autophagy flux and lipid droplet degradation in lysosomes induced by TGF-beta. Pretreatment with the autophagy inducer rapamycin reversed the effects of AMPK, further confirming that AICAR inhibited TGF-beta-induced HSC activation via the regulation of autophagy flux. Our study indicates that AICAR exerts its anti-fibrotic and anti-lipid depletion effect, at least in part, by inhibiting TGF-beta-induced autophagy flux.