Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 304, Issue 1, Pages G26-G37Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00064.2012
Keywords
adeno-associated virus; Ect2; gene repression; hepatocyte proliferation; liver regeneration
Categories
Funding
- National Institutes of Health [P20 RR-021940]
- American Association for the Study of Liver Disease/American Liver Foundation Liver Scholar Award
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR021940] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available