Hepatic insulin resistance directly promotes formation of cholesterol gallstones

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Abstract
People with the metabolic syndrome often develop gallstones. Why these two disorders are linked has not been not clear, but now Kahn and his colleagues have shown that lack of insulin signaling in the liver leads to dysregulation of genes that control the transport and synthesis of bile acids, thus altering the proper profile of bile salts and resulting in the formation of gallstones. 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.