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Hepatocyte nuclear factor-1α is an essential regulator of bile acid and plasma cholesterol metabolism

Nature Genetics volume 27, pages 375–382 (2001)Cite this article

Abstract

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-1α (encoded by TCF1). Tcf1−/− mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1−/− mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1−/− liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1−/− mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1α) also regulates transcription of the gene (Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1−/− mice. Increased plasma cholesterol of Tcf1−/− mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism.

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Figure 1: Steady-state mRNA levels of genes that are regulated by Tcf1.
Figure 2: Western-blot analysis of bile acid transporters and Fxr in liver protein extracts.
Figure 3: The Nr1h4 (Fxr-1) promoter is activated by Tcf1.
Figure 4: Bile acid concentrations are increased in the serum, stool and urine of Tcf1−/− mice.
Figure 5: Tcf1 is a transcriptional activator of the ileal bile acid transporter gene (Slc10a2).
Figure 6: The Slc10a2 promoter is activated by Tcf1.
Figure 7: Identification of an abnormal lipoprotein particle in Tcf1−/− mice.
Figure 8: Large, buoyant HDL is an abundant, apoE-enriched lipoprotein particle in hypercholesterolemic Tcf1−/− mice.

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Acknowledgements

We thank J.M. Friedman and P. Cohen for advice on gene expression analysis and for discussions; D. Levine and E. Ribary for apoB48/b100 and apoA1 measurements; A. Wolkoff for Oatp1 antibody; J. Lingutla for technical help; E. Sphicas for electron microscopy services; and R. and H. Heilbrunn and A. and F.B. Adler for support. This work was supported in part by the American Diabetes Association (M.S.), NIH grants R01DK55033-01 (M.S.), HD20632 (M.A.), DK02076 (B.S.), DK26756 (S.S.) and NIH MSTP grant GM07739 (D.Q.S.), Deutsche Studienstiftung (M.B.), Emerald Foundation (M.S.) and AMDEK.

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Authors and Affiliations

  1. Laboratorie of Metabolic Diseases, The Rockefeller University, New York, New York, USA

    David Q. Shih, Markus Bussen & Markus Stoffel

  2. Laboratorie of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York, USA

    Ephraim Sehayek & Jan L. Breslow

  3. Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA

    Meenakshisundaram Ananthanarayanan, Benjamin L. Shneider & Frederick J. Suchy

  4. Department of Medicine, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA

    Sarah Shefer & Jaya S. Bollileni

  5. National Cancer Institute, Bethesda, Maryland, USA

    Frank J. Gonzalez

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Shih, D., Bussen, M., Sehayek, E. et al. Hepatocyte nuclear factor-1α is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet 27, 375–382 (2001). https://doi.org/10.1038/86871

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