SREBP: Gatekeeper of Cholesterol Homeostasis

Mon, 07/29/2013 - 10:38

SREBP1 (sterol-regulatory-element-binding protein 2) is a basic-helix-loop-helix-leucine zipper (bHLH-ZIP) transcription factor. It regulates sterol and cholesterol homeostasis by controlling enzymes involved in cholesterol synthesis and uptake, e.g. HMG-CoA. The SREBP1 antibody was used in fundamental studies to dissect SREBP1 domains and downstream signaling (1). These studies identified domains for membrane attachment, DNA binding and transcriptional activation of effectors like the sterol regulatory element-1 (SRE-1) and Max, another bHLH-ZIP protein. SREBP1 modulates expression of the transmembrane protein ABCA1 (ATP-binding cassette transporter-A1) that is responsible for managing cellular cholesterol efflux.  ABCA1 mediates transport of lipids between the Golgi body and plasma membrane, as well as cholesterol and phospholipid efflux to the ApoA1 and ApoE apolipoproteins in the formation of high-density lipoprotein (HDL). Work with SREBP1 antibody in liver, adipose tissue, and skeletal muscle studied the involvement of SREBP-1 during fasting and refeeding and found that SREBP-1 is involved not only in lipid metabolism but glucose metabolism and energy homeostasis (2). Researchers have used the SREBP1 antibody to identify genes responsible for transcriptional regulation through both SREBP2 and SREBP1 (3). Biochemical studies with SREBP1 antibody found that   cholesterol regulates the rate-limiting fatty acid synthesis pathway enzyme stearoyl-CoA desaturase (SCD) gene family independently of SREBP-1 maturation (4). The accessory protein Insig-2, found in the endoplasmic reticulum (ER), inhibits the escort of SREBPs to the Golgi in a sterol-dependent fashion (5).  This feedback regulation adds a level of fine-tuning to the cholesterol homeostasis system.

  1. PMID: 8006035
  2. PMID: 15627654
  3. PMID: 7862668
  4. PMID: 12364560
  5. PMID: 12242332

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