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Molecular and Cellular Biology, November 2000, p. 8264-8282, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Elevated Levels of Hepatocyte Nuclear Factor 3beta in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis

Francisco M. Rausa,1 Yongjun Tan,1 Heping Zhou,1 Kyung W. Yoo,1 Donna Beer Stolz,2 Simon C. Watkins,2 Roberta R. Franks,1 Terry G. Unterman,1,3 and Robert H. Costa1,*

Departments of Molecular Genetics, Medicine, Physiology, and Biophysics, College of Medicine, University of Illinois at Chicago,1 and VA West Side Medical Center,3 Chicago, Illinois 60607-7170, and Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 152612

Received 9 March 2000/Returned for modification 2 May 2000/Accepted 12 July 2000

The winged helix transcription factor, hepatocyte nuclear factor-3beta (HNF-3beta ), mediates the hepatocyte-specific transcription of numerous genes important for liver function. However, the in vivo role of HNF-3beta in regulating these genes remains unknown because homozygous null HNF3beta mouse embryos die in utero prior to liver formation. In order to examine the regulatory function of HNF-3beta , we created transgenic mice in which the -3-kb transthyretin promoter functions to increase hepatocyte expression of the rat HNF-3beta protein. Postnatal transgenic mice exhibit growth retardation, depletion of hepatocyte glycogen storage, and elevated levels of bile acids in serum. The retarded growth phenotype is likely due to a 20-fold increase in hepatic expression of insulin-like growth factor binding protein 1 (IGFBP-1), which results in elevated levels in serum of IGFBP-1 and limits the biological availability of IGFs required for postnatal growth. The defects in glycogen storage and serum bile acids coincide with diminished postnatal expression of hepatocyte genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glycogen synthase) and sinusoidal bile acid uptake (Ntcp), respectively. These changes in gene transcription may result from the disruptive effect of HNF-3beta on the hepatic expression of the endogenous mouse HNF-3alpha ,-3beta , -3gamma , and -6 transcription factors. Furthermore, adult transgenic livers lack expression of the canalicular phospholipid transporter, mdr2, which is consistent with ultrastructure evidence of damage to transgenic hepatocytes and bile canaliculi. These transgenic studies represent the first in vivo demonstration that the HNF-3beta transcriptional network regulates expression of hepatocyte-specific genes required for bile acid and glucose homeostasis, as well as postnatal growth.

* Corresponding author. Mailing address: Department of Molecular Genetics (M/C 669), University of Illinois at Chicago, College of Medicine, 900 S. Ashland Ave., Rm. 2220 MBRB, Chicago, IL 60607-7170. Phone: (312) 996-0474. Fax: (312) 355-4010. E-mail: RobCosta{at}uic.edu.

Molecular and Cellular Biology, November 2000, p. 8264-8282, Vol. 20, No. 21
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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