Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding.
Sterol 27-hydroxylase (CYP27) participates in the conversion of cholesterol to bile acids. We examined lipid metabolism in mice lacking the Cyp27 gene. On normal rodent chow, Cyp27(-/-) mice have 40% larger livers, 45% larger adrenals, 2-fold higher hepatic and plasma triacylglycerol concentrations, a 70% higher rate of hepatic fatty acid synthesis, and a 70% increase in the ratio of oleic to stearic acid in the liver versus Cyp27(+/+) controls. In Cyp27(-/-) mice, cholesterol 7alpha-hydroxylase activity is increased 5-fold, but bile acid synthesis and pool size are 47 and 27%, respectively, of those in Cyp27(+/+) mice. Intestinal cholesterol absorption decreases from 54 to 4% in knockout mice, while fecal neutral sterol excretion increases 2.5-fold. A compensatory 2.5-fold increase in whole body cholesterol synthesis occurs in Cyp27(-/-) mice, principally in liver, adrenal, small intestine, lung, and spleen. The mRNA for the cholesterogenic transcription factor sterol regulatory element-binding protein-2 (SREBP-2) and mRNAs for SREBP-2-regulated cholesterol biosynthetic genes are elevated in livers of mutant mice. In addition, the mRNAs encoding the lipogenic transcription factor SREBP-1 and SREBP-1-regulated monounsaturated fatty acid biosynthetic enzymes are also increased. Hepatic synthesis of fatty acids and accumulation of triacylglycerols increases in Cyp27(-/-) mice and is associated with hypertriglyceridemia. Cholic acid feeding reverses hepatomegaly and hypertriglyceridemia but not adrenomegaly in Cyp27(-/-) mice. These studies confirm the importance of CYP27 in bile acid synthesis and they reveal an unexpected function of the enzyme in triacylglycerol metabolism.
Repa
J J
JJ
Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Lund
E G
EG
Horton
J D
JD
Leitersdorf
E
E
Russell
D W
DW
Dietschy
J M
JM
Turley
S D
SD
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005704:Gallbladder / Q000378:metabolism; D006529:Hepatomegaly / Q000235:genetics*; D015228:Hypertriglyceridemia / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D009929:Organ Size; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics
D001647:Bile Acids and Salts; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D014280:Triglycerides; C030104:lipoprotein cholesterol; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D019826:Cholic Acid