Hepatocyte-specific deletion of hepatocyte nuclear factor-4? in adult mice results in increased hepatocyte proliferation.

ABSTRACT: Hepatocyte nuclear factor-4? (HNF4?) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4? may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4? knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4? in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4? resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4? target genes involved in hepatic differentiation. Interestingly, ?500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4?, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4? at three of these genes. Furthermore, overexpression of HNF4? in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4? actively inhibits hepatocyte proliferation by repression of specific promitogenic genes.

SUBMITTER: Walesky C 

PROVIDER: S-EPMC3543634 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature