The Diet1 locus confers protection against hypercholesterolemia through enhanced bile acid metabolism.
The C57BL/6ByJ (B6By) mouse strain is resistant to diet-induced hypercholesterolemia and atherosclerosis, despite its near genetic identity with the atherosclerosis-susceptible C57BL/6J (B6J) strain. We previously identified a genetic locus, Diet1, which is responsible for the resistant phenotype in B6By mice. To investigate the function of Diet1, we compared mRNA expression profiles in the liver of B6By and B6J mice fed an atherogenic diet using a DNA microarray. These studies revealed elevated expression levels in B6By liver for key bile acid synthesis proteins, including cholesterol 7alpha-hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor alpha. Expression levels for several other genes involved in bile acid metabolism were subsequently found to differ between B6By and B6J mice, including the bile acid receptor farnesoid X receptor, oxysterol 7alpha-hydroxylase, sterol-12alpha-hydroxylase, and hepatic bile acid transporters on both sinusoidal and canalicular membranes. The overall expression profile of the B6By strain suggests a higher rate of bile acid synthesis and transport in these mice. Consistent with this interpretation, fecal bile acid excretion is increased 2-fold in B6By mice, and bile acid levels in blood and urine are elevated 3- and 18-fold, respectively. Genetic analysis of serum bile acid levels revealed co-segregation with Diet1, indicating that this locus is likely responsible for both increased bile acid excretion and resistance to hypercholesterolemia in B6By mice.
Phan
Jack
J
Department of Medicine, UCLA and the Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
Pesaran
Tina
T
Davis
Richard C
RC
Reue
Karen
K
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002874:Chromosome Mapping; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D014644:Genetic Variation; D006937:Hypercholesterolemia / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D013250:Steroid Hydroxylases / Q000235:genetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C095122:multidrug resistance protein 3; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse