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J. Biol. Chem., Vol. 275, Issue 50, 39685-39692, December 15, 2000
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From the 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
Disruption of the Sterol 27-Hydroxylase Gene in Mice Results in
Hepatomegaly and Hypertriglyceridemia
REVERSAL BY CHOLIC ACID FEEDING*
,
,, and
Departments of Internal Medicine and
§ Molecular Genetics, Howard Hughes Medical
Institute, Department of Pharmacology, University of Texas Southwestern
Medical Center, Dallas, Texas 75390 and the ** Department of Medicine,
Center for Research, Prevention and Treatment of Atherosclerosis,
Hadassah University Hospital, 91120 Jerusalem, Israel
/ 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 7
-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.
*
This work was supported by National Institutes of Health
Grants HL 09610 and HL 20948, the Moss Heart Fund, Robert A. Welch Foundation Grant I-0971, the Perot Family Foundation, the William M. Keck Foundation, the Howard Hughes Medical Institute (to J. J. R.), and the American Digestive Health Foundation Industry Research Scholar Award (to J. D. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Internal
Medicine, The University of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-8887. Tel.: 214-648-8773; Fax: 214-648-9761; E-mail:
stephen.turley@utsouthwestern.edu.
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