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Molecular and Cellular Biology, February 2001, p. 1393-1403, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1393-1403.2001

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

Graham P. Hayhurst,1 Ying-Hue Lee,1,dagger Gilles Lambert,2 Jerrold M. Ward,3 and Frank J. Gonzalez1,*

Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute,1 and Metabolic Disease Branch, National Heart, Lung and Blood Institute,2 National Institutes of Health, Bethesda, Maryland 20892, and Office of Laboratory Animal Resources, National Cancer Institute, National Institutes of Health, Frederick, Maryland 217023

Received 5 July 2000/Returned for modification 29 August 2000/Accepted 31 October 2000

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 1alpha [HNF1alpha ], -1beta , -3alpha , -3beta , -3gamma , -4alpha , and -6 and members of the c/ebp family). Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1alpha -null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4alpha -null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4alpha is indispensable for hepatocyte differentiation. However, the function of HNF4alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4alpha 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 HNF4alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.

* Corresponding author. Mailing address: Building 37, Room 3E-24, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-9067. Fax: (301) 496-8419. E-mail: fjgonz{at}helix.nih.gov.

dagger Present address: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.

Molecular and Cellular Biology, February 2001, p. 1393-1403, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1393-1403.2001


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