Recent research has provided significant information regarding the molecular and cellular basis for the development of hepatic fibrosis that can lead to cirrhosis, and need for liver transplantation. Our work in the prior funding period focused on the role of two key adipocytokines-leptin and adiponectin-in which we have convincingly demonstrated that leptin is clearly a pro-fibrogenic cytokine while adiponectin prohibits fibrosis. Our preliminary data and the current proposal are consistent with the long-term objectives of this laboratory: to understand basic mechanisms associated with chronic liver wound-healing. Adiponectin promotes a molecular environment in hepatic stellate cells (HSCs)-e.g. reduced tissue inhibitor of metalloproteinase I [TIMPI] expression that favors dissolution of dense extracellular matrix, the basis for the pathogenesis of cirrhosis. In vitro, adiponectin treated HSCs blocked leptin-mediated signal transduction that leads to pro-fibrogenic responses and required adiponectin receptor 1, but does not appear to depend entirely on adenosine monophosphate kinase (AMPK). The overall goal of the current proposal is to determine the potential mechanisms whereby adiponectin can promote resolution of hepatic fibrosis since there is evidence advanced fibrosis is reversible. The central hypothesis of this proposal is that adiponectin promotes the resolution of hepatic fibrosis by inhibiting activation of focal adhesion kinase (FAK), preventing formation of focal adhesions (FAs), which results in the suppression of key fibrogenic properties of the activated HSC. The central hypothesis will be tested by the following three hypothesis- driven specific aims:
SPECIFIC AIM 1 : To determine that adiponectin suppresses FAK activation thereby preventing formation of FAs in activated HSCs and inhibits genes associated with hepatic fibrosis. Preliminary data reveal adiponectin prevents phosphorylation of FAK by the protein tyrosine phosphatase, SHP-2;and adiponectin prevents FA assembly both in vitro and in vivo.
SPECIFIC AIM 2 : To demonstrate that adiponectin activation of activator protein 1 (AP-1) is the mechanism responsible for adiponectin's transcriptional activation of matrix metalloproteinases (MMPs) MMP-1/13;and, for inhibiting ?(I) collagen gene transcription through deactivation of FAK. Preliminary data demonstrate that adiponectin increases MMP-1/13 mRNA and respective promoter activity;but, small hairpin RNA against FAK (shFAK) blocks ?2(I) collagen gene expression in spite of the presence of globular adiponectin (gAd) in vitro.
SPECIFIC AIM 3 : To elucidate, by in vivo and ex vivo approaches, the mechanisms whereby adiponectin reverses HSC activation, promotes HSC senescence, and ultimately leads to resolution of fibrosis. Preliminary data indicate that while CCl4 treated adiponectin knock-out mice develop FAs as assessed by immunofluorescence, adenoviral delivery of adiponectin suppressed FA assembly;and, ex vivo, adiponectin markedly suppresses HSC- alpha smooth muscle actin (?-SMA) expression.

Public Health Relevance

Cirrhosis is a leading cause of death in the United States. Previously our work demonstrated that one hormone-like substance, leptin, can contribute to liver scar formation-which can lead to cirrhosis;while, another hormone-like substance, adiponectin, can help prevent or aide in resolving liver scar formation. The work proposed will provide a molecular basis for the use of adiponectin in drug development for liver scar formation that leads to cirrhosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062092-10A1
Application #
8502913
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2002-07-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$339,300
Indirect Cost
$121,800
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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