Hepatic insulin resistance directly promotes formation of cholesterol gallstones

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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.

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Figure 1: LIRKO mice are susceptible to cholesterol gallstone formation.
Figure 2: LIRKO mice show quantitative and qualitative defects in bile acid synthesis on a chow diet.
Figure 3: Biliary cholesterol content is increased in LIRKO mice, promoting supersaturated bile.
Figure 4: Insulin regulates Abcg5 and Abcg8 expression through FoxO1.

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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.).

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Correspondence to Sudha B Biddinger.

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Supplementary Fig. 1, Supplementary Tables 1–4 and Supplementary Methods (PDF 203 kb)

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Biddinger, S., Haas, J., Yu, B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 14, 778–782 (2008) doi:10.1038/nm1785

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