Oleate Potentiates Oxysterol Inhibition of Transcription from Sterol Regulatory Element-1-regulated Promoters and Maturation of Sterol Regulatory Element-binding Proteins

Abstract

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.

Transcytosis of Albumin in Astrocytes Activates the Sterol Regulatory Element-binding Protein-1, Which Promotes the Synthesis of the Neurotrophic Factor Oleic Acid

“…Oleic acid protects SREBP-1 proteolysis by preventing the cleavage and release of low molecular mass SREBP-1 mature form (15)(16)(17), which induces the enzymes involved in oleic acid synthesis (11,12,18). In this context, our results show that albumin increases the amount of the low molecular mass SREBP-1 mature form, whereas it decreases that of the high molecular mass SREBP-1 inactive precursor (Fig.…”

“…Because oleic acid protects SREBP-1 from proteolysis (15)(16)(17), it is reasonable to suggest that the effect of albumin would be brought about by sequestration of the fatty acid in the ER. In agreement with this, when the sequestration of oleic acid was prevented by the addition of albumin already containing oleic acid, SREBP-1 cleavage and the increase in SCD mRNA were abolished (Fig.…”

“…A critical committed step in the synthesis of oleic acid is the introduction of the cis-double bond in the ⌬ 9 position, catalyzed by SCD, an enzyme also located in the ER that is transcriptionally activated by SREBP-1 because its gene contains the SRE (14). Oleic acid synthesis is feedback-regulated because oleic acid suppresses SREBP-1 activation (15)(16)(17) and SCD induction (18), both of which accompany the decrease in oleic acid synthesis (19).…”

Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins

“…In 293 and other cultured mammalian cells, proteolysis of SREBP-1a and SREBP-2 has been shown to be induced by cholesterol withdrawal (21,29,30). Moreover, growth in medium lacking unsaturated fatty acids promotes the activation of SREBP-1a and SREBP-1c͞ADD1 (24,31,32).…”

Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms

“…The mechanism by which oleate mediates or induces SREBP-1c and lipogenic gene expression remains to be explored. Several in vitro studies have shown that oleate suppresses the proteolytic processing of SREBP-1 protein and reduces SREBP-1 and lipogenic gene expression (52)(53)(54). The inhibitory effect has been proposed to be attributed to the increase in the release of ceramide from sphingomyelin (55).…”