Letter abstract
Nature Medicine 14, 778 - 782 (2008)
Published online: 29 June 2008 | doi:10.1038/nm1785
Hepatic insulin resistance directly promotes formation of cholesterol gallstones
Sudha B Biddinger1,2, Joel T Haas1, Bian B Yu3, Olivier Bezy1, Enxuan Jing1, Wenwei Zhang4, Terry G Unterman4, Martin C Carey3,5,6 & C Ronald Kahn1,3,6
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.
- Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA.
- Division of Endocrinology, 300 Longwood Avenue, Children's Hospital, Boston, Massachusetts 02115, USA.
- Gastroenterology Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
- Departments of Medicine, Physiology and Biophysics, University of Illinois at Chicago College of Medicine and Jesse Brown VA Medical Center, 820 South Damen Avenue, Chicago, Illinois 60612, USA.
- Department of Medicine, 25 Shattuck Street, Harvard Medical School, Boston, Massachusetts 02115, USA.
- These authors contributed equally to this work.
Correspondence to: Sudha B Biddinger1,2 e-mail: sudha.biddinger@joslin.harvard.edu
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