The understanding of molecular mechanisms that underlie myofibroblastic transdifferentiation (MTD) of hepatic stellate cells (HSC), is a prerequisite for development of new therapeutic modalities for alcoholic liver cinliosis. We have approached this goal from a unique standpoint of cell fate regulation of pluripotent mesenchymal cells. In this end, we discovered "adipogenic regulation" is essential for HSC quiescence and loss of this regulation results in MTD. As such, restoration ofthe expression of PPAR?, the master regulator of adipogenesis in MFB achieves a phenotypic reversal of the cells to quiescent HSC, and this effect is completely abrogated by co-transduction of a dominant negative mutant of PPAR?. In search for the mechanisms of PPAR? repression in MTD, an international collaboration by Tsukamoto and Mann laboratories disclosed major contributions of two epigenetic regulators: the methyl CpG binding protein MeCP2 which causes HP1a recmitment to methylated H3K9 at PPAR? promoter;and the polycomb repressive complex 2 (PRC2) methyltransferase EZH2 which di- and tri-methylate H3K27 as another mechanism of powerful gene silencing. We also demonstrates a loss ofthe negative control with miR132 as a novel mechanism of MeCP2 induction which in turn positively regulates the expression of EZH2 in MTD. The proposed collaborative research is aimed at extending these ground-breaking findings on epigenetic regulation of MTD shown in culture-activated HSC, to MTD in alcoholic liver fibrogenesis. Toward this goal, the following specific aims will be pursued: 1) to determine whether MeCP2 and EZH2 mediated epigenetic mechanisms are evident in activated HSC/MFB isolated from the mouse model of alcoholic liver fibrosis;2) to determine whether MeCP2 knockout or a EZH2 inhibitor specifically targeted to activated HSC/MFB ameliorates alcoholic liver fibrosis;3) to validate MeCP2 and EZH2 mediated epigenetic regulation in activated HSC/MFB in alcoholic liver fibrosis in man. We believe that the proposed study will uncover novel mechanisms of alcoholic liver fibrosis and important therapeutic targets for the disease. PUBLIC HELATH

Public Health Relevance

The proposed international collaboration will disclose new information conceming how alcohol-induced cirrhosis of the liver develops and will test novel therapeutic approaches for the disease in animal models. It is our long-term goal that such treatment options will be made available for patients suffering from cirrhosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA018663-04
Application #
8522248
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Gao, Peter
Project Start
2010-09-01
Project End
2015-08-30
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$338,012
Indirect Cost
$89,907
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Page, Agata; Paoli, Pier; Moran Salvador, Eva et al. (2016) Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol 64:661-73
Chen, Jian; Yao, Zhi-Xing; Chen, Jiun-Sheng et al. (2016) TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. J Clin Invest 126:527-42
Kweon, Soo-Mi; Chi, Feng; Higashiyama, Reiichi et al. (2016) Wnt Pathway Stabilizes MeCP2 Protein to Repress PPAR-γ in Activation of Hepatic Stellate Cells. PLoS One 11:e0156111
Eguchi, Akiko; Lazaro, Raul G; Wang, Jiaohong et al. (2016) Extracellular vesicles released by hepatocytes from gastric infusion model of ALD contain a miRNA barcode that can be detected in blood. Hepatology :
Tsukamoto, Hidekazu (2015) Metabolic reprogramming and cell fate regulation in alcoholic liver disease. Pancreatology 15:S61-5
Page, Agata; Paoli, Pier P; Hill, Stephen J et al. (2015) Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J Hepatol 62:388-97
Fung, Eileen; Tsukamoto, Hidekazu (2015) Morphogen-related therapeutic targets for liver fibrosis. Clin Res Hepatol Gastroenterol 39 Suppl 1:S69-74
Zeybel, Müjdat; Hardy, Timothy; Robinson, Stuart M et al. (2015) Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics 7:25

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