SREBP1a and SREBP1c isoforms predominantly activate the expression of genes involved in fatty acid synthesis and the SREBP2 isoform upregulates genes that increase cellular cholesterol by de novo synthesis and exogenous uptake ( Horton et al., 2002).
Cleavage results in the release of the N-terminal fragment of SREBP into the cytoplasm, which translocates to the nucleus to bind to DNA and initiate gene transcription. When cellular cholesterol levels decrease, the SCAP-SREBP complex translocates to the Golgi where SREBP is proteolytically cleaved by proteases, S1P and S2P. At sufficient cellular cholesterol levels, SREBP is retained as a full-length protein in the endoplasmic reticulum (ER) bound to adaptor proteins SREBP cleavage-activating protein (SCAP) and inhibitory insulin-induced gene (INSIG) ( Brown and Goldstein, 1997). Cellular lipid and cholesterol homeostasis are tightly regulated by the transcription factor sterol response element binding protein (SREBP). It is becoming increasingly appreciated that there exists a connection between cellular immunity and cholesterol. Indeed, the vascular endothelium is a primary sensor of the circulating bloodstream and is exposed to various stimuli that regulate systemic host defense responses. NF-κB, along with other activated transcription factors, such as activator protein 1 (AP1) upregulate the transcription of several inflammatory response genes that increase (1) vascular permeability, (2) leukocyte chemoattraction, and (3) immune cell adhesion and extravasation into tissue ( Pober and Sessa, 2007). Inflammatory cytokines, such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL1β), bind to their respective receptors to activate I-κ-kinase, which phosphorylates and degrades inhibitory IκBα and releases the key inflammatory transcription factor, NF-κB, to the nucleus ( DiDonato et al., 1997). Endothelial cells (ECs) are in constant contact with the bloodstream and rapidly change their phenotype in response to inflammatory stimuli. However, the endothelium plays a significant role in the overall inflammatory response, particularly in initiation and vascular maintenance. Undoubtedly, leukocytes are crucial for host defense and tissue repair, regulating the balance between resolution and chronic inflammation. The majority of the biological processes regulating acute inflammation has focused on the contribution of tissue-infiltrating leukocytes. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC. Detailed analysis of NF-κB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Furthermore, SREBP2 activation was dependent on NF-κB DNA binding and canonical SCAP-SREBP2 processing. Treatment of primary human ECs with pro-inflammatory cytokines upregulated SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Here, we studied the role of cholesterol and a key transcription regulator of cholesterol homeostasis, SREBP2, in the EC responses to inflammatory stress. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes however, this relationship has not been deeply explored in the vascular endothelium.
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