Journal
HEPATOLOGY
Volume 47, Issue 2, Pages 677-685Publisher
WILEY
DOI: 10.1002/hep.21991
Keywords
-
Categories
Funding
- NIAAA NIH HHS [R01 AA15055] Funding Source: Medline
- NIGMS NIH HHS [R01 GM041804] Funding Source: Medline
Ask authors/readers for more resources
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 [H-3]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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available