We studied bile acid and cholesterol metabolism in insulin-dependent diabetes utilizing genetically modified mice unable to synthesize cholic acid (Cyp8bl-/-). Diabetes was induced in Cyp8bl-/- and wild type animals (Cyp8bl+/+) 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 Cyp8bl+/+ mice fed cholesterol, while diabetic Cyp8bl-/- mice did not show any aberrations regardless of the diet. Diabetic cholesterol-fed Cyp8bl+/+ 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. (c) 2006 Elsevier Inc. All rights reserved.