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J Biol Chem, Vol. 273, Issue 33, 21402-21407, August 14, 1998
From the Department of Biochemistry and Molecular Biology, East
Tennessee State University, James H. Quillen College of Medicine,
Johnson City, Tennessee 37614-0581
Activation of genes containing SRE-1
(sterol regulatory element
1) sequences is known to be under the regulation of sterols through modulation of the proteolytic maturation of SREBPs
(SRE-1-binding proteins). Previous
work has demonstrated SREBP-mediated transcriptional activation of
genes encoding enzymes of sterol and fatty acid biosynthesis. Because
synthesis of both sterols and C18 fatty acids are required for cell
growth, in the absence of exogenous supplements of these lipids, we
examined the hypothesis that fatty acid can also be regulatory in SREBP
maturation. Our data indicate that C18 fatty acids can potentiate the
biological activities of a typical, regulatory sterol:
25-hydroxycholesterol. Inhibition of C18 fatty acid synthesis in cells
cultured in serum-free medium renders them resistant to killing by
25-hydroxycholesterol. Repression of expression of reporter constructs
driven by promoters bearing SRE-1 element(s) by 25-hydroxycholesterol
is increased by C18 fatty acid supplementation. C18 fatty acids also
increase the inhibitory effect of 25-hydroxycholesterol on proteolytic
maturation and nuclear localization of SREBPs. Furthermore, we also
show that C18 fatty acid supplementation can enhance the inhibitory effect of 25-hydroxycholesterol on sterol and fatty acid biosynthesis. These results demonstrate that maximal down-regulation of SREBP maturation and the consequent repression of SRE-1 promoters occurs in
response to both a regulatory sterol and fatty acid.
Oleate Potentiates Oxysterol Inhibition of Transcription from
Sterol Regulatory Element-1-regulated Promoters and Maturation of
Sterol Regulatory Element-binding Proteins
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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