SREBPmediated

SREBP-mediated regulation refers to the transcriptional control of lipid biosynthesis pathways by sterol regulatory element-binding proteins (SREBPs). The SREBP family comprises SREBP-1a, SREBP-1c, and SREBP-2, with distinct but overlapping roles: SREBP-1c largely drives fatty acid synthesis genes, SREBP-2 mainly activates cholesterol biosynthetic genes, and SREBP-1a has broad transcriptional activity.

SREBPs are membrane-bound transcription factors located in the endoplasmic reticulum. They form a complex with SCAP and are retained in the ER by INSIG proteins when cellular sterol levels are high. When sterol stores are depleted, SCAP escorts SREBP to the Golgi apparatus, where the proteases site-1 protease (S1P) and site-2 protease (S2P) cleave the protein. The liberated N-terminal domain then translocates to the nucleus and binds sterol regulatory elements in target gene promoters, activating transcription of enzymes involved in lipid and cholesterol synthesis such as HMG-CoA reductase, HMG-CoA synthase, acetyl-CoA carboxylase, and fatty acid synthase.

Activity of SREBP is modulated by nutritional and hormonal signals. Insulin signaling and nutrient abundance promote SREBP-1c expression and processing, in part via mTORC1, while energy stress and AMPK activation can suppress SREBP maturation. Tissue distribution includes liver, adipose tissue, and to a lesser extent other organs, coordinating systemic lipid homeostasis.

Dysregulation of SREBP-mediated pathways contributes to metabolic disorders, including non-alcoholic fatty liver disease, obesity, and dyslipidemia. Therapeutic strategies targeting SREBP signaling aim to balance lipid production, though broad essential functions pose challenges.