NDLI: Hepatocyte Nuclear Factor 4α (Nuclear Receptor 2A1) Is Essential for Maintenance of Hepatic Gene Expression and Lipid Homeostasis

Content Provider	PubMed Central
Author	Hayhurst, Graham P. Lee, Ying-hue Lambert, Gilles Ward, Jerrold M. Gonzalez, Frank J.
Copyright Year	2001
Abstract	The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1α [HNF1α], -1β, -3α, -3β, -3γ, -4α, and -6 and members of the c/ebp family). Of these, only HNF4α (nuclear receptor 2A1) and HNF1α appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1α-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4α-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4α is indispensable for hepatocyte differentiation. However, the function of HNF4α in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4α in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4α expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4α is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.
Related Links	http://dx.doi.org/10.1128/mcb.21.4.1393-1403.2001
Ending Page	1403
Page Count	11
Starting Page	1393
File Format	PDF
ISSN	02707306
e-ISSN	10985549
Journal	Molecular and Cellular Biology
Issue Number	4
Volume Number	21
Language	English
Publisher	American Society for Microbiology
Publisher Date	2001-02-15
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology

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