High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate–activated protein kinase

Abstract

UNLABELLED: Adiponectin is an adipocyte-derived, antidiabetic, antiatherogenic adipocytokine that is present in serum as 3 isoforms. Decreased plasma adiponectin levels are closely associated with the severity of nonalcoholic fatty liver diseases. This study was designed to elucidate a role of adiponectin and its mediator adenosine monophosphate-activated protein kinase (AMPK) on proliferation of activated hepatic stellate cells (HSCs), the key cells promoting fibrosis. Immortalized human HSC line hTERT and primary rat HSCs were stimulated with platelet-derived growth factor (PDGF) with or without pretreatment with AMPK activator 5-aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR), metformin, or high molecular weight (HMW) adiponectin. HMW adiponectin dose-dependently suppressed PDGF-induced HSC proliferation. Adenoviral transduction with dominant-negative AMPK (DN-AMPK) abolished the suppressive effect of adiponectin in HSCs. AICAR, metformin, or transduction of constitutively active AMPK attenuated PDGF-induced [(3)H]thymidine incorporation, which was abolished by either a chemical AMPK inhibitor or transduction of DN-AMPK, consistent with an antiproliferative effect of AMPK. The suppressive effect of AMPK on HSC proliferation is mediated through multiple mechanisms, including (1) an inhibition of the AKT pathway, (2) inhibition of NADPH oxidase-dependent reactive oxygen species (ROS) production via induction of antioxidant enzymes, and (3) an increase in the expression of the cyclin-dependent kinase inhibitors p27(kip1) and p21(cip1). CONCLUSION: Adiponectin inhibits HSC proliferation via activation of AMPK. AMPK activation by AICAR or metformin inhibits HSC proliferation via suppression of ROS production and subsequent inhibition of AKT pathway. Thus, adiponectin and AMPK inhibit HSC proliferation and hepatic fibrosis via multiple molecular mechanisms.