SREBP

Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors that regulate lipid biosynthesis. In mammals, the SREBP gene family includes SREBP-1a, SREBP-1c and SREBP-2, encoded by SREBF1 and SREBF2. SREBP-1a is a potent trans-activator; SREBP-1c predominates in liver and adipose tissue and mainly controls fatty acid synthesis, whereas SREBP-2 largely controls cholesterol synthesis. All SREBPs are synthesized as inactive polypeptides anchored in the endoplasmic reticulum (ER) membrane as part of a complex with SREBP cleavage-activating protein (SCAP). The ER retention of the complex is reinforced by INSIG proteins in the presence of sterols.

When cellular sterol levels fall, INSIG dissociates from SCAP, allowing the SCAP-SREBP complex to travel to the Golgi apparatus. In the Golgi, site-1 protease (S1P) and site-2 protease (S2P) cleave SREBP, releasing the N-terminal transcription factor domain. This active domain translocates to the nucleus, where it binds sterol regulatory elements (SREs) in target gene promoters and induces transcription of lipogenic genes, including those involved in cholesterol biosynthesis (for example HMGCR, DHCR24) and fatty acid synthesis (for example ACACA, FASN, SCD1).

Regulation of SREBP activity is influenced by nutritional and hormonal signals. Insulin promotes SREBP-1c processing via the mTORC1 pathway, enhancing lipogenesis, while high sterol levels promote INSIG-mediated retention of SREBP in the ER. Dysregulation of SREBP pathways is linked to metabolic diseases such as obesity, type 2 diabetes, and nonalcoholic fatty liver disease, highlighting SREBP’s central role in lipid homeostasis.