Abstract
The early growth response (EGR) family of transcription factors has been implicated in control of lipid biosynthetic genes. Egr1 is induced by insulin both in vitro and in vivo and is the most highly expressed family member in liver. In this study, we investigated whether Egr1 regulates cholesterol biosynthetic genes in liver. Using an insulin-sensitive liver cell line, we show that localization of Egr1 to cholesterol biosynthetic genes is induced by insulin treatment and that this localization precedes the induction of the genes. Reduction in Egr1 expression using targeted siRNA blunted the insulin-dependent induction of cholesterol genes. A similar reduction in squalene epoxidase expression was also observed in Egr1 null mice. In addition, application of chromatin immunoprecipitation (ChIP) samples to tiled gene microarrays revealed localization of Egr1 in promoter regions of many cholesterol gene loci. In vivo ChIP assays using liver tissue show that Egr1 localization to several cholesterol biosynthetic gene promoters is induced by feeding. Finally, analysis of plasma cholesterol in Egr1(-/-) mice indicated a significant decrease in serum cholesterol when compared with wild-type mice. Together these data point to Egr1 as a modulator of the cholesterol biosynthetic gene family in liver.
Highlights
Ported to the Golgi in response to cholesterol depletion where proteolytic cleavage frees the N-terminal portion of sterol-response element-binding proteins (SREBPs) to translocate to the nucleus to activate transcription
The ratelimiting enzyme in cholesterol biosynthesis, was induced in H4IIEs following insulin treatment, and this induction coincided with the induction of Egr1 (Fig. 1A)
SREBPs play a central role in transcriptional regulation of lipid biosynthetic genes [35], there is substantial evidence that other factors contribute to regulation of this gene network by hormonal signals such as insulin
Summary
Ported to the Golgi in response to cholesterol depletion where proteolytic cleavage frees the N-terminal portion of SREBPs to translocate to the nucleus to activate transcription (reviewed in Ref. 2). In vivo binding analyses have suggested relatively little insulin-induced change in SREBP-2 binding to genes involved in cholesterol biosynthesis [9, 10] Such studies have led to a proposed model in which SREBP-2 may promote insulin regulation of cholesterol biosynthetic genes by maintaining target promoters in a receptive state for binding of additional, insulin-dependent transcription factors [5]. In the Krox20/Egr null mouse, the expression of Hmgcr and Cyp was significantly reduced (Ͼ80%) in peripheral nerve despite little change in SREBP levels, suggesting a role for EGR factors in the regulation of cholesterol metabolism. Egr Regulates Cholesterol Synthesis the identification of a polymorphism in the human EGR1 promoter linked to lower serum cholesterol levels [18] These studies suggest that EGR factors may modulate expression of cholesterol biosynthetic genes in peripheral nerve myelin and in liver. We suggest that Egr acts in concert with SREBP factors to mediate the insulin-dependent induction of cholesterol biosynthesis in liver
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