Critical role of cholic acid for development of hypercholesterolemia and gallstones in diabetic mice.
We studied bile acid and cholesterol metabolism in insulin-dependent diabetes utilizing genetically modified mice unable to synthesize cholic acid (Cyp8b1-/-). Diabetes was induced in Cyp8b1-/- and wild type animals (Cyp8b1+/+) by alloxan, and the mice were fed normal or cholesterol-enriched diet for 10 weeks. The serum levels of cholesterol were strongly increased in diabetic Cyp8b1+/+ mice fed cholesterol, while diabetic Cyp8b1-/- mice did not show any aberrations regardless of the diet. Diabetic cholesterol-fed Cyp8b1+/+ mice had much higher biliary cholesterol and cholesterol saturation index than all other groups, their bile contained a large number of cholesterol crystals, and their canalicular cholesterol transporter Abcg5/g8 mRNA levels were much higher. Cyp7a1 mRNA levels were similar in all diabetic mice but higher compared to non-diabetic animals. The results indicate a critical role for cholic acid for the development of hypercholesterolemia and gallstones in our animal model.
Wang
Jin
J
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Gåfvels
Mats
M
Rudling
Mats
M
Murphy
Charlotte
C
Björkhem
Ingemar
I
Einarsson
Curt
C
Eggertsen
Gösta
G
D000496:Alloxan; D000818:Animals; D002791:Cholesterol, Dietary / Q000378:metabolism*; D019826:Cholic Acid / Q000172:deficiency / Q000378:metabolism*; D048909:Diabetes Complications / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D042882:Gallstones / Q000209:etiology / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism*; D008297:Male; D051379:Mice
D002791:Cholesterol, Dietary; D000496:Alloxan; D019826:Cholic Acid