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Hepatocyte Nuclear Factor 4 alpha (HNF4α) Knockdown Stimulates Pro‐Mitogenic Gene Expression in Hepatocytes
Author(s) -
Walesky Chad Michael,
Gunewardena Sumedha,
Edwards Genea,
Apte Udayan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.274.7
Subject(s) - gene knockdown , hepatocyte nuclear factor 4 , hepatocyte , hepatocyte nuclear factors , cell growth , biology , hepatocyte growth factor , gene expression , microbiology and biotechnology , gene , cancer research , in vitro , transcription factor , genetics , nuclear receptor , receptor
HNF4α, the master regulator of hepatocyte differentiation, has been shown to inhibit hepatocyte proliferation via yet to be identified mechanisms. We investigated the mechanisms of HNF4α‐induced inhibition of hepatocyte proliferation using two novel HNF4α knockdown mouse models. Hepatocyte specific deletion of HNF4α resulted in increased hepatocyte proliferation. Comparative global gene expression analysis revealed a set of genes commonly regulated in both HNF4α deletion models. The majority of the down‐regulated genes are known HNF4α target genes involved in hepatic differentiation. Interestingly, many up‐regulated genes were associated with cell proliferation and cancer. HNF4α knockdown mice treated with the known hepatic carcinogen diethylnitrosamine developed a 7‐fold increase in number of tumors, as compared to controls. Furthermore, in vitro over expression of HNF4α in mouse HCC cells resulted in a decrease in cell proliferation along with a decrease in promitogenic gene expression. Taken together these data indicate that HNF4α inhibits hepatocyte proliferation by repression of specific pro‐mitogenic genes.