Hepatic insulin resistance directly promotes formation of cholesterol gallstones.
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.
Biddinger
Sudha B
SB
Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA. sudha.biddinger@joslin.harvard.edu
Haas
Joel T
JT
Yu
Bian B
BB
Bezy
Olivier
O
Jing
Enxuan
E
Zhang
Wenwei
W
Unterman
Terry G
TG
Carey
Martin C
MC
Kahn
C Ronald
CR
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002769:Cholelithiasis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D000072474:Cytochrome P450 Family 7; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002784:Cholesterol; D002791:Cholesterol, Dietary; D000072474:Cytochrome P450 Family 7; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008074:Lipoproteins; D011972:Receptor, Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C467200:Foxo1 protein, mouse; C097207:Cyp7b1 protein, mouse