Genomics

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SREBP2 regulates endothelial response to inflammation via direct transcriptional activation of KLF6


ABSTRACT: Cholesterol homeostasis plays a central role in disease pathogenesis in chronic disorders such as cardiovascular and kidney diseases. The transcription factor SREBP2 is the main regulator of cholesterol metabolism and is central to the mechanism of action of lipid lowering drugs, such as statins, that are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic cardiovascular disease. Recently, SREBP2 has been implicated in both the innate and adaptive immune responses by upregulation of cholesterol flux or via direct transcriptional activation of pro-inflammatory genes in leukocytes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and are activated in response to damage and inflammation. The loss of SREBP2 in cultured human ECs results in significant alterations of the transcriptional response to inflammatory cytokines whereas SREBF2 knockdown inhibits the transcription and secretion of pro-inflammatory chemokines but amplifies type I interferon response genes. Furthermore, we show that SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake, but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing (ChIP-seq) of endogenous SREBP2 reveals the SREBP2 bound to the promoter regions of classical response genes as well as two non-classical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. Overexpression of SREBP2 upregulated both BHLHE40 and KLF6 transcripts independent of inflammatory stress and the transcription of these genes were found to be sensitive to cellular cholesterol levels. Of these two targets, we found that KLF6 was responsible for the amplification of chemokine expression highlighting a tight relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223094 | GEO | 2023/08/21

REPOSITORIES: GEO

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