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

Hepatocyte-specific deletion of hepatocyte nuclear factor-4 alpha in adult mice results in increased hepatocyte proliferation. Am J Physiol Gastrointest Liver Physiol 304: G26-G37, 2013. First published October 25, 2012; doi: 10.1152/ajpgi.00064.2012.-Hepatocyte nuclear factor-4 alpha (HNF4 alpha) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4 alpha may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4 alpha knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4 alpha in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4 alpha resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4 alpha 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 alpha, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4 alpha at three of these genes. Furthermore, overexpression of HNF4 alpha 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 alpha actively inhibits hepatocyte proliferation by repression of specific promitogenic genes.