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Hepatic insulin resistance directly promotes formation of cholesterol gallstones.

Abstract

Despite the well-documented association between gallstones and the metabolic syndrome, 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) 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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  • Authors+Show Affiliations

    ,

    Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA. sudha.biddinger@joslin.harvard.edu

    , , , , , , ,

    Source

    Nature medicine 14:7 2008 Jul pg 778-82

    MeSH

    ATP Binding Cassette Transporter, Subfamily G, Member 5
    ATP Binding Cassette Transporter, Subfamily G, Member 8
    ATP-Binding Cassette Transporters
    Animals
    Bile Acids and Salts
    Cholelithiasis
    Cholesterol
    Cholesterol, Dietary
    Cytochrome P450 Family 7
    DNA-Binding Proteins
    Forkhead Box Protein O1
    Forkhead Transcription Factors
    Insulin Resistance
    Lipoproteins
    Liver
    Male
    Metabolic Syndrome
    Mice
    Mice, Knockout
    Mice, Transgenic
    Models, Animal
    Receptor, Insulin
    Receptors, Cytoplasmic and Nuclear
    Steroid Hydroxylases
    Transcription Factors

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    18587407

    Citation

    Biddinger, Sudha B., et al. "Hepatic Insulin Resistance Directly Promotes Formation of Cholesterol Gallstones." Nature Medicine, vol. 14, no. 7, 2008, pp. 778-82.
    Biddinger SB, Haas JT, Yu BB, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008;14(7):778-82.
    Biddinger, S. B., Haas, J. T., Yu, B. B., Bezy, O., Jing, E., Zhang, W., ... Kahn, C. R. (2008). Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nature Medicine, 14(7), pp. 778-82. doi:10.1038/nm1785.
    Biddinger SB, et al. Hepatic Insulin Resistance Directly Promotes Formation of Cholesterol Gallstones. Nat Med. 2008;14(7):778-82. PubMed PMID: 18587407.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hepatic insulin resistance directly promotes formation of cholesterol gallstones. AU - Biddinger,Sudha B, AU - Haas,Joel T, AU - Yu,Bian B, AU - Bezy,Olivier, AU - Jing,Enxuan, AU - Zhang,Wenwei, AU - Unterman,Terry G, AU - Carey,Martin C, AU - Kahn,C Ronald, Y1 - 2008/06/29/ PY - 2008/04/07/received PY - 2008/05/12/accepted PY - 2008/7/1/pubmed PY - 2008/8/16/medline PY - 2008/7/1/entrez SP - 778 EP - 82 JF - Nature medicine JO - Nat. Med. VL - 14 IS - 7 N2 - Despite the well-documented association between gallstones and the metabolic syndrome, 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) 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. SN - 1546-170X UR - https://www.unboundmedicine.com/medline/citation/18587407/full_citation L2 - http://dx.doi.org/10.1038/nm1785 DB - PRIME DP - Unbound Medicine ER -