Figure 1. Mechanistic insight into the cholesterol homeostasis: Sterol regulatory element binding protein (SREBP-2) is the key modulator of cholesterol biosynthesis. Endoplasmic reticulum (ER) is in center where SREBP-2 is synthesized but for the activation, its translocation is required to the Golgi. In the ER, SREBP-cleavage activating protein (SCAP) interacts with the SREBP-2. Upper panel: In case of normal cholesterol in ER, SCAP interacts with SREBP-2, allowing COPII to bind SCAP which is responsible for the movement of SCAP-SREBP complex from ER to Golgi. In the Golgi SREBP-2 undergoes proteolytic cleavage by site 1 protease (S1P) and S2P, thereby releasing the active domain that enters into nucleus and binds with the sterol regulatory element (SRE) in the promoter, eventually, activates transcription of target genes such as HMG-R, LDL-R, and PCSK-9. HMG-R normally regulates the cholesterol biosynthesis. LDL-Rs are present on the surface of hepatocytes that clear the excess cholesterol via adopting LDL particle and leads to the lysosomal degradation. After the degradation of LDL, the LDL-R are recycled back to the surface of hepatocyte for repeated clearance of circulatory LDL. Lower panel: In case of excess cholesterol, INSIG binds to the SCAP and detachment of COPII occurs. Due to the detachment of COPII, SREBP-2 are retained in ER which restricts further processing of SREBP-2. Lack of processed SREBP-2 under elevated cholesterol conditions results in altered HMG-R and LDL-R expression as well as activity, whereas, HNF-1α continues to stimulate the expression of PCSK-9, which binds to the LDL-R and leads to its lysosomal degradation that restricts the LDL clearance from the blood.