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J. Biol. Chem., Vol. 276, Issue 20, 17576-17583, May 18, 2001
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From the Department of Internal Medicine and Department of Veterans
Affairs, University of Iowa, Iowa City, Iowa 52242
A control chow diet or diets containing 1%
cholesterol (cholesterol-enriched) or 4% cholestyramine and 0.15%
lovastatin (cholesterol-depletion) were fed to hamsters for 2 weeks. Sterol regulatory element-binding protein (SREBP)-1a, SREBP-1c,
SREBP-2, 3-hydroxy-3-methylglutaryl-coenzyme A reductase,
3-hydroxy-3-methylglutaryl-coenzyme A synthase, and LDL receptor
mRNA levels and SREBP-1 and -2 protein expression were estimated in
villus cell populations from duodenum, jejunum, and ileum. SREBP-1a was
a minor transcript in hamster intestine, and its gene expression was
not altered by changes in dietary cholesterol flux. In contrast,
SREBP-1c gene expression was increased by dietary cholesterol and
decreased by cholesterol depletion. mRNA levels for SREBP-2 and the
other sterol-responsive genes were increased in intestines of animals
on the cholesterol depletion diet but minimally suppressed if at all,
by the diet enriched in cholesterol. In general, the amount of the
precursor form of SREBP-1 was higher in cells of the upper villus and
lower in cells of the lower villus. SREBP-2 precursor was higher in
cells of the lower villus and lower in cells of the upper villus.
Protein expression of precursor correlated with the location of gene
expression for SREBPs. The amount of precursor mass of SREBP-2 was not
altered by cholesterol feeding but was increased by cholesterol
depletion. The mature form of SREBP-2 was in very low abundance and
difficult to detect in intestines of animals fed control chow or
cholesterol. It was readily detectable and increased in intestines of
animals on the cholesterol-depletion diet. The diets did not
significantly alter the amount of precursor or mature forms of SREBP-1.
Cholesterol feeding had no effect on cholesterol or fatty acid
synthesis, whereas synthesis of these lipids was increased in
intestines of hamsters on the cholesterol-depleted diet. These results
suggest that SREBP-1a has little or no role in regulating intestinal
cholesterol synthesis. It is postulated that under basal conditions,
SREBP-1c regulates intestinal fatty acid synthesis and SREBP-2
regulates cholesterol synthesis. Following marked changes in
cholesterol flux across the intestine, SREBP-2 assumes the role of
SREBP-1 and regulates both cholesterol and fatty acid synthesis in intestine.
Regulation of Sterol Regulatory Element-binding Proteins in
Hamster Intestine by Changes in Cholesterol Flux*
,
*
This work was supported by the Department of Veterans
Affairs and National Institutes of Health Grants HL49264 and 56032.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. Tel.:
319-356-2579; Fax: 319-353-6399; E-mail:
f-jeffrey-field@uiowa.edu.
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