Abstract
Despite the well-documented association between gallstones and the metabolic syndrome1,2, the mechanistic links between these two disorders remain unknown. Here we show that mice solely with hepatic insulin resistance, created by liver-specific disruption of the insulin receptor (LIRKO mice)3 are markedly predisposed toward cholesterol gallstone formation due to at least two distinct mechanisms. Disinhibition of the forkhead transcription factor FoxO1, increases expression of the biliary cholesterol transporters Abcg5 and Abcg8, resulting in an increase in biliary cholesterol secretion. Hepatic insulin resistance also decreases expression of the bile acid synthetic enzymes, particularly Cyp7b1, and produces partial resistance to the farnesoid X receptor, leading to a lithogenic bile salt profile. As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection. Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106, 3143–3421 (2002).
Diehl, A.K. Cholelithiasis and the insulin resistance syndrome. Hepatology 31, 528–530 (2000).
Michael, M.D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).
Everhart, J.E., Khare, M., Hill, M. & Maurer, K.R. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 117, 632–639 (1999).
Sandler, R.S. et al. The burden of selected digestive diseases in the United States. Gastroenterology 122, 1500–1511 (2002).
Osler, W. The Principles and Practice of Medicine 432 (D. Appleton and Company, New York, 1892).
Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).
Biddinger, S.B. et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 7, 125–134 (2008).
Heuman, D.M. Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J. Lipid Res. 30, 719–730 (1989).
Moschetta, A., Bookout, A.L. & Mangelsdorf, D.J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med. 10, 1352–1358 (2004).
Kok, T. et al. Enterohepatic circulation of bile salts in farnesoid X receptor–deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid–binding protein. J. Biol. Chem. 278, 41930–41937 (2003).
Chen, Q., Amaral, J., Biancani, P. & Behar, J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology 116, 678–685 (1999).
Graf, G.A. et al. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J. Biol. Chem. 278, 48275–48282 (2003).
Yu, L. et al. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J. Biol. Chem. 280, 8742–8747 (2005).
Repa, J.J. et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J. Biol. Chem. 277, 18793–18800 (2002).
Remaley, A.T. et al. Comparative genome analysis of potential regulatory elements in the ABCG5-ABCG8 gene cluster. Biochem. Biophys. Res. Commun. 295, 276–282 (2002).
Foufelle, F. & Ferre, P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem. J. 366, 377–391 (2002).
Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).
Kodama, S., Koike, C., Negishi, M. & Yamamoto, Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol. Cell. Biol. 24, 7931–7940 (2004).
Jiang, Z.Y. et al. Increased expression of LXRα, ABCG5, ABCG8 and SR-BI in the liver from normolipidemic, nonobese Chinese gallstone patients. J. Lipid Res. 49, 464–472 (2008).
Uppal, H. et al. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization. Hepatology 47, 1331–1342 (2008).
Akiyoshi, T., Uchida, K., Takase, H., Nomura, Y. & Takeuchi, N. Cholesterol gallstones in alloxan-diabetic mice. J. Lipid Res. 27, 915–924 (1986).
Shaffer, E.A. & Small, D.M. Biliary lipid secretion in cholesterol gallstone disease. The effect of cholecystectomy and obesity. J. Clin. Invest. 59, 828–840 (1977).
Bennion, L.J. & Grundy, S.M. Effects of obesity and caloric intake on biliary lipid metabolism in man. J. Clin. Invest. 56, 996–1011 (1975).
Ishida, H., Yamashita, C., Kuruta, Y., Yoshida, Y. & Noshiro, M. Insulin is a dominant suppressor of sterol 12 α-hydroxylase P450 (CYP8B) expression in rat liver: possible role of insulin in circadian rhythm of CYP8B. J. Biochem. 127, 57–64 (2000).
Carey, M.C. & Leonard, M.R. Pathophysiology of bile secretion. in Future Perspectives in Gastroenterology Falk Sym. Vol. 161 (eds. Carey, M.C., Díte, P., Gabryelewicz, A., Keim, V. & Mössner, J.) 77–96 (Springer, Heidelberg, in the press).
Grundy, S.M., Lan, S.P. & Lachin, J. The effects of chenodiol on biliary lipids and their association with gallstone dissolution in the National Cooperative Gallstone Study (NCGS). J. Clin. Invest. 73, 1156–1166 (1984).
Attili, A.F. et al. Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis. Hepatology 26, 809–818 (1997).
Biddinger, S.B. et al. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Diabetes 54, 1314–1323 (2005).
Yu, L. et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA 99, 16237–16242 (2002).
Acknowledgements
We thank C. Rask-Madsen for photography and M. Leonard and D. Cohen for helpful discussions. We also thank H. Hobbs (University of Texas Southwestern Medical Center at Dallas) for antibodies to ABCG5 and ABCG8, T. Willson (GlaxoSmithKline) for supplying GW4064 and J. Sakai (University of Tokyo) for the ABCG5 and ABCG8 luciferase reporter constructs. This work was funded in part by grants from the US National Institutes of Health, including DK063696-05 (S.B.B.), DK31036 and DK45935 (C.R.K.), DK036588 and DK073687 (M.C.C.), the Joslin Diabetes and Endocrine Research Center grant DK036836-20 and the Veterans Affairs Merit Review Program (T.G.U.).
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Fig. 1, Supplementary Tables 1–4 and Supplementary Methods (PDF 203 kb)
Rights and permissions
About this article
Cite this article
Biddinger, S., Haas, J., Yu, B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 14, 778–782 (2008). https://doi.org/10.1038/nm1785
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1785
This article is cited by
-
Association between weight-adjusted-waist index and gallstones: an analysis of the National Health and Nutrition Examination Survey
BMC Gastroenterology (2024)
-
Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating cholesterol and bile acid metabolism in an FXR-dependent manner
Chinese Medicine (2024)
-
Erhöhtes Risiko für gastrointestinale Erkrankungen bei Typ-2-Diabetes
Gastro-News (2024)
-
Metabolic dysfunction-associated gallstone disease: expecting more from critical care manifestations
Internal and Emergency Medicine (2023)
-
Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis
Science China Life Sciences (2023)