Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia

Joyce J. Repa, Erik G. Lund, Jay D. Horton, Eran Leitersdorf, David W. Russell, John M. Dietschy, Stephen D. Turley

Research output: Contribution to journalArticle

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Abstract

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-l- 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 7α-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.

Original languageEnglish (US)
Pages (from-to)39685-39692
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number50
DOIs
StatePublished - Dec 15 2000

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Cholestanetriol 26-Monooxygenase
Hepatomegaly
Hypertriglyceridemia
Genes
Liver
Sterol Regulatory Element Binding Protein 2
Bile Acids and Salts
Cholesterol
Triglycerides
Messenger RNA
Transcription Factors
Fatty Acids
Cholesterol 7-alpha-Hydroxylase
Cholic Acid
Monounsaturated Fatty Acids
Sterols
Enzymes
Metabolism
Intestinal Absorption
Plasmas

ASJC Scopus subject areas

  • Biochemistry

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Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. / Repa, Joyce J.; Lund, Erik G.; Horton, Jay D.; Leitersdorf, Eran; Russell, David W.; Dietschy, John M.; Turley, Stephen D.

In: Journal of Biological Chemistry, Vol. 275, No. 50, 15.12.2000, p. 39685-39692.

Research output: Contribution to journalArticle

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abstract = "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-l- 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 7α-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.",
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