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J. Biol. Chem., Vol. 277, Issue 6, 3878-3885, February 8, 2002
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From the A major physiological feedback
mechanism of cholesterol in transcription of a number of lipid
metabolism-related genes is mediated by sterol regulatory elements
(SREs) and their binding proteins (SREBPs). Polyunsaturated free fatty
acids alone, as well as synergistically with sterols, decrease
SRE-mediated gene expression up to 80% in a dose-dependent
manner by decreasing levels of the active transcription factor SREBP.
We investigated potential mechanisms for this effect. We hypothesized
that free fatty acids reduce SREBP-mediated gene transcription by
increasing intracellular cholesterol content through the hydrolysis of
cellular sphingomyelin, which has a high affinity for free cholesterol. We also questioned whether the lipid second messenger ceramide, a
product of sphingomyelin hydrolysis, can decrease SRE-mediated gene
transcription. First we investigated the effect of fatty acids on
sphingomyelin hydrolysis. Incubation of
[3H]choline-labeled cells with unsaturated (but not
saturated) fatty acids induced hydrolysis of
[3H]choline-labeled sphingomyelin. Also, incubation of
cell extracts from fatty acid-treated cells with
[3H]sphingomyelin increased generation of
[3H]ceramide compared with control cells
in vitro. We found that addition of ceramide analogs alone
and additively with fatty acids decreased SRE expression and that
ceramide analogs reduced levels of the transcriptionally active forms
of SREBP-1 and SREBP-2. Increasing intracellular ceramide levels by
exogenous sphingomyelinase or inhibition of ceramidase decreased
SRE-mediated gene expression. None of the above conditions induced
apoptosis. Incubation with U18666A, a compound that inhibits
intracellular cholesterol movement, increased SRE-mediated gene
transcription. C2-ceramide abrogated the effect of
U18666A on SRE-mediated gene transcription, suggesting cholesterol-independent regulation of SREBP. We provide evidence that
sphingomyelin hydrolysis and intermediates of sphingomyelin metabolism
(in addition to cholesterol and fatty acids) contribute to regulation
of SRE-mediated gene transcription.
Unsaturated Fatty Acid-mediated Decreases in Sterol Regulatory
Element-mediated Gene Transcription Are Linked to Cellular Sphingolipid
Metabolism*
§¶,,
,§
Institute of Human Nutrition and
the § Department of Pediatrics, Columbia University, New
York, New York 10032 and the ** Department of Clinical
Chemistry, University of Freiburg, 79106 Freiburg, Germany
*
This work was supported in part by National Institutes of
Health Grant HL40404.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.
Supported in part by National Institutes of Health Training
Grant HL07343-22.
To whom correspondence should be addressed: Inst. of Human
Nutrition, Columbia University, 630 W. 168th St., PH 1512, New York, NY
10032. Tel.: 212-305-4808; Fax: 212-305-3079; E-mail: rjd20@columbia.edu.
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