FIGURE 2.

Regulation of cholesterol synthesis. The central transcription factor of cholesterol synthesis in cells is SREBP2, which is regulated in multiple layers and controls the synthesis of key enzymes in cholesterol synthesis. SREBP2 binds to SCAP in the ER. When the cholesterol level is less than 5% of the ER, SCAP binds to the COPII protein and escorts SREBP2 from the ER to the Golgi and anchors via adipoQ receptor 3 (PAQR3) in the Golgi, where site 1 and site 2 proteases (S1P, S2P) cleave the luminal loop of SREBP2 to release the N-terminal domain that enters the nucleus. In the nucleus, SREBP2 activates multiple cholesterol synthesis genes by binding to the SRE. Additionally, the INSIG proteins dissociate from SCAP, and HMGCR and SM are less bound and ubiquitylated by E3 ubiquitin ligase and degraded by the proteasome. When the cholesterol level is more than 5% of the ER, the INSIGs are recruited by SCAP to form the SCAP–SREBP2–INSIG complex, and the complex holds in the ER further by ERLINs and TRC8. Additionally, cholesterol induces the E3 ligase complex to ubiquitylate HMGCR and SM.