FIGURE 1.

(A) Subcellular localization of the cholesterol biosynthetic pathway in mammalian cells. Blue fonts indicate SREBP-2-regulated cholesterol biosynthetic enzymes. With the exception of HMGCR, all enzymes for the conversion of acetyl-CoA to farnesyl diphosphate contain functional peroxisomal targeting signals. Acetyl-CoA derived from peroxisomal β-oxidation of very long-chain fatty acids and dicarboxylic acids is channeled to cholesterol synthesis inside peroxisomes (Weinhofer et al., 2006; Kovacs et al., 2007). Farnesyl diphosphate leaves the peroxisomes and is converted either to cholesterol in the ER or to nonsterol isoprenoids. The conversion of acetyl-CoA to HMG-CoA also occurs in the cytoplasm. The mitochondrial and peroxisomal acetoacetyl-CoA thiolase and the cytosolic and peroxisomal HMG-CoA synthase are encoded by single genes, respectively. In hepatocytes, the conversion of cholesterol to bile acids also partly takes place in peroxisomes. The primary C₂₄-bile acids are formed from C₂₇-bile acid intermediates by peroxisomal β-oxidation of the side chain, followed by conjugation of the C₂₄-bile acids to glycine or taurine by the peroxisomal enzyme BAAT. Figure modified from Figure 1 in Faust and Kovacs (2014). (B) Regulation of the SREBP-2 pathway. The precursor SREBP-2 is embedded as inactive transcription factor in ER membranes. In the presence of cholesterol and hydroxysterols (e.g., 25-hydroxycholesterol, 27-hydroxycholesterol), the SCAP-SREBP-2 complex is retained in the ER by interaction with INSIG proteins. Whereas cholesterol binds to SCAP and induces a conformational change in SCAP through which it binds to INSIGs, hydroxysterols bind to INSIGs and cause INSIGs to bind to SCAP. In the absence of sterols, INSIGs dissociate from SCAP, whereupon the INSIGs are ubiquitinated and degraded in proteasomes. The SCAP-SREBP-2 complex is loaded into COPII-coated vesicles and transported to the Golgi. In the Golgi SREBPs are processed sequentially by Site-1 and Site-2 proteases to release the N-terminal transcription factor domain that then enters the nucleus and activates SRE (sterol regulatory element)-containing genes. Figure modified from Figure 2 in Faust and Kovacs (2014).