Abstract
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.
Highlights
From the Department of Medicine, UCLA and the Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073
Elevated Expression of Bile Acid Metabolism Genes in B6By Mice—Our previous work established that resistance of B6By mice to diet-induced hypercholesterolemia and atherosclerosis is not a result of reduced food consumption or reduced cholesterol absorption compared with B6J mice [5]
Hepatic mRNA isolated from B6J and B6By mice fed the Ath diet for 3 weeks was hybridized to arrays containing more than 18,000 mouse cDNA sequences, approximately one-third of which represent known genes and the remainder derived from expressed sequence tags (ESTs)
Summary
Vol 277, No 1, Issue of January 4, pp. 469 –477, 2002 Printed in U.S.A. The Diet Locus Confers Protection against Hypercholesterolemia through Enhanced Bile Acid Metabolism*. To investigate the function of Diet, 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 7␣hydroxylase and sterol-27-hydroxylase, and the oxysterol nuclear receptor liver X receptor ␣. B6By mice exhibited altered expression levels for additional bile acid synthetic enzymes, bile acid transporters from both the sinusoidal and canalicular membranes, and the bile acid-responsive nuclear receptor, farnesoid X receptor (FXR) These results suggest that more efficient conversion of cholesterol to bile acids and increased bile secretion may contribute to the lower plasma cholesterol levels in B6By mice. We determined that elevated bile acid levels segregate with Diet, indicating that this locus determines both the resistance to hypercholesterolemia and increased bile acid excretion in B6By mice
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