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

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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References

  1. Tranche, T. et al. Hepatocyte nuclear factor-1 (HNF1) and liver gene expression. in Liver Gene Expression (eds. Tronche, F. & Yaniv, M.) 155–181 (R.G. Landes, Austin, 1994).

    Google Scholar 

  2. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young. Nature 384, 455–458 (1996).

    Article  CAS  Google Scholar 

  3. Pontoglio, M. et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 84, 575–585 (1996).

    Article  CAS  Google Scholar 

  4. Lee, Y.H., Sauer, B. & Gonzalez, F.J. Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1α knockout mouse. Mol. Cell. Biol. 18, 3059–3068 (1998).

    Article  CAS  Google Scholar 

  5. Brown, M.S. & Goldstein, J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis by proteolysis of a membrane bound transcription factor. Cell 89, 331–340 (1997).

    Article  CAS  Google Scholar 

  6. Muller, M. & Jansen, P.L. Molecular aspects of hepatobiliary transport. Am. J. Physiol. 272, G1285–1303 (1997).

    CAS  Google Scholar 

  7. Chawla, A., Saez, E. & Evans, R.M. Don't know much bile-ology. Cell 103, 1–4 (2000).

    Article  CAS  Google Scholar 

  8. Meier, P.J., Eckhardt, U., Schroeder, A., Hagenbuch, B. & Stieger, B. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver. Hepatology 26, 1667–1677 (1997).

    Article  CAS  Google Scholar 

  9. Stiewger, B. & Meier, P.J. Bile acid and xenobiotic transporters in liver. Curr. Opin. Cell. Biol. 10, 462–467 (1998).

    Article  Google Scholar 

  10. de Vree, J.M. et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc. Natl. Acad. Sci. USA 95, 282–287 (1998).

    Article  CAS  Google Scholar 

  11. Chiang, J.Y.L. Regulation of bile acid synthesis. Front. Biosci. 3, D176–D193 (1997).

    Article  Google Scholar 

  12. Janowski, B.A., Willy, P.J., Devi, T.R., Falck, J.R. & Mangelsdorf, D.J. An oxysterol signaling pathway mediated by the nuclear receptor LXRa. Nature 383, 728–731 (1996).

    Article  CAS  Google Scholar 

  13. Peet, D.J. et al. Cholesterol and bile acid metabolisms are impaired in mice lacking the nuclear oxysterol receptor LXR α. Cell 93, 693–704 (1998).

    Article  CAS  Google Scholar 

  14. Makishima, M. et al. Identification of a nuclear receptor for bile acids. Science 284, 1362–1365 (1999).

    Article  CAS  Google Scholar 

  15. Parks, D.J. et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365–1368 (1999).

    Article  CAS  Google Scholar 

  16. Nitta, M., Ku, S., Brown, C., Okamoto, A.Y. & Shan, B. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7a-hydroxylase gene. Proc. Natl. Acad. Sci. USA 96, 6660–6665 (1999).

    Article  CAS  Google Scholar 

  17. Goodwin, B. et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6, 517–526 (2000).

    Article  CAS  Google Scholar 

  18. Lu, T.T. et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6, 507–515 (2000).

    Article  CAS  Google Scholar 

  19. Sinal, C.J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000).

    Article  CAS  Google Scholar 

  20. Powell, D.R. & Suwanichkul, A. HNF1 activates transcription of the human gene for insulin-like growth factor binding protein-1. DNA Cell Biol. 12, 283–289 (1993).

    Article  CAS  Google Scholar 

  21. Wong, M.H., Oelkers, P., Craddock, A.L. & Dawson, P.A. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J. Biol. Chem. 269, 1340–1347 (1994).

    CAS  PubMed  Google Scholar 

  22. Christie, D.M., Dawson, P.A., Thevananther, S. & Shneider, B.L. Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum. Am. J. Physiol. 271, G377–385 (1996).

    CAS  PubMed  Google Scholar 

  23. Ishibashi, S., Goldstein, J.L., Brown, M.S., Herz, J. & Burns, D.K. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J. Clin. Invest. 93, 1885–1893 (1994).

    Article  CAS  Google Scholar 

  24. Felker, T.E., Hamilton, R.L. & Havel, R.J. Secretion of lipoprotein-X by perfused livers of rats with cholestasis. Proc. Natl. Acad. Sci. USA 75, 3459–3463 (1978).

    Article  CAS  Google Scholar 

  25. Manzato, E. et al. Formation of lipoprotein-X. Its relationship to bile compounds. J. Clin. Invest. 57, 1248–1260 (1976).

    Article  CAS  Google Scholar 

  26. Norum, K.R., Glomset, J.A., Nichols, A.V. & Forte, T. Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: physical and chemical of low and high-density lipoproteins. J. Clin. Invest. 50, 1131–1140 (1971).

    Article  CAS  Google Scholar 

  27. van Antwerpen, R. et al. Cryo-electron microscopy of low-density lipoprotein and reconstituted discoidal high density lipoprotein: imaging of the apolipoprotein moiety. J. Lipid Res. 38, 659–669 (1997).

    CAS  PubMed  Google Scholar 

  28. Laggner, P. et al. The lipid bilayer structure of the abnormal human plasma lipoprotein X. An X-ray small-angle-scattering study. Eur. J. Biochem. 77, 165–171 (1977).

    Article  CAS  Google Scholar 

  29. Austin, M.A. & Edwards, K.L. Small, dense low-density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr. Opin. Lipidol. 7, 167–171 (1996).

    Article  CAS  Google Scholar 

  30. Homanics, G.E. et al. Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. J. Biol. Chem. 270, 2974–80 (1995).

    Article  CAS  Google Scholar 

  31. Föger, B. et al. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J. Biol. Chem. 274, 36912–36920 (1999).

    Article  Google Scholar 

  32. Mahley, R.W., Weisgraber, K.H., Innerarity, T., Brewer, H.B., Jr. & Assmann, G. Swine lipoproteins and atherosclerosis. Changes in the plasma lipoproteins and apoproteins induced by cholesterol feeding. Biochemistry 14, 2817–2823 (1975).

    Article  CAS  Google Scholar 

  33. Stolz, A. et al. cDNA cloning of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family. J. Biol. Chem. 268, 10448–10457 (1993).

    CAS  PubMed  Google Scholar 

  34. Stoffel, M. & Duncan, S.A. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism. Proc. Natl. Acad. Sci. USA 94, 13209–13214 (1997).

    Article  CAS  Google Scholar 

  35. Ananthanarayanan, M., Bucuvalas, J.C., Shneider, B.L., Sippel, C.J. & Suchy, F.J. An ontogenically regulated 48-kDa protein is a component of the Na(+)-bile acid cotransporter of rat liver. Am. J. Physiol. 261, G810–817 (1991).

    CAS  PubMed  Google Scholar 

  36. Bergwerk, A.J. et al. Immunologic distribution of an organic anion transport protein in rat liver and kidney. Am. J. Physiol. 271, G231–238 (1996).

    CAS  PubMed  Google Scholar 

  37. Mendel, D.B., Hansen, L.P., Graves, M.K., Conley, P.B. & Crabtree, G.R. HNF-1 α and HNF-1 β (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev. 5, 1042–1056 (1991).

    Article  CAS  Google Scholar 

  38. Setchell, K.D.R., Lawson, A.M., Tanida, N. & Sjovall, J. General methods for the analysis of metabolic profiles of bile acids and related compounds in feces. J. Lipid Res. 24, 1085–1100 (1983).

    CAS  PubMed  Google Scholar 

  39. Setchell, K.D.R. et al. Δ22-Ursodeoxycholic acid, a unique metabolite of administered ursodeoxycholic acid in rats, indicating partial β-oxidation as a major pathway for bile acid metabolism. Biochemistry 34, 4169–4178 (1995).

    Article  CAS  Google Scholar 

  40. Aalto-Setala, K. et al. Intestinal expression of human apolipoprotein A-IV in transgenic mice fails to influence dietary lipid absorption or feeding behavior. J. Clin. Invest. 93, 1776–1786 (1994).

    Article  CAS  Google Scholar 

  41. Sehayek, E. et al. Biliary cholesterol excretion: a novel mechanism that regulates dietary cholesterol absorption. Proc. Natl. Acad. Sci. USA 95, 10194–10199 (1998).

    Article  CAS  Google Scholar 

  42. Levine, D.M. & Williams, K.J. Automated measurements of mouse apolipoprotein B: convenient screening tool for mouse models of atherosclerosis. Clin. Chem. 43, 669–674 (1997).

    CAS  PubMed  Google Scholar 

  43. Shneider, B.L. et al. Cloning and characterization of a novel peptidase from rat and human ileum. J. Biol. Chem. 272, 31006–31015 (1997).

    Article  CAS  Google Scholar 

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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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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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