Dna

released domain of SREBP migrates to nucleus

Transcription of target genes is activated

FIGURE 21-43 SREBP activation. Sterol regulatory element-binding proteins (SREBPs, shown in green) are embedded in the ER when first synthesized, in a complex with the protein SREBP cleavage-activating protein (SCAP, red). (N and C represent the amino and carboxyl termini of the proteins.) When bound to SCAP, SREBPs are inactive. When

Transcription of target genes is activated sterol levels decline, the complex migrates to the Golgi complex, and SREBP is cleaved by two different proteases in succession. The liberated amino-terminal domain of SREBP migrates to the nucleus, where it activates transcription of sterol-regulated genes.

unsaturated fatty acids, is controlled by a small family of proteins called sterol regulatory element-binding proteins (SREBPs). When newly synthesized, these proteins are embedded in the ER. Only the soluble amino-terminal domain of an SREBP functions as a transcrip-tional activator, using mechanisms discussed in Chapter 28. However, this domain has no access to the nucleus and cannot participate in gene activation while it remains part of the SREBP molecule. To activate transcription of the HMG-CoA reductase gene and other genes, the transcriptionally active domain is separated from the rest of the SREBP by proteolytic cleavage. When cholesterol levels are high, SREBPs are inactive, secured to the ER in a complex with another protein called SREBP cleavage-activating protein (SCAP) (Fig. 21-43). It is SCAP that binds cholesterol and a number of other sterols, thus acting as a sterol sensor. When sterol levels are high, the SCAP-SREBP complex probably interacts with another protein that retains the entire complex in the ER. When the level of sterols in the cell declines, a conformational change in SCAP causes release of the SCAP-SREBP complex from the ER-retention activity, and the complex migrates within vesicles to the Golgi complex. In the Golgi complex, SREBP is cleaved twice by two different proteases, the second cleavage releasing the amino-terminal domain into the cytosol. This domain travels to the nucleus and activates transcription of its target genes. The amino-terminal domain of SREBP has a short half-life and is rapidly degraded by proteasomes (see Fig. 27-42). When sterol levels increase sufficiently, the proteolytic release of SREBP amino-terminal domains is again blocked, and proteasome degradation of the existing active domains results in a rapid shut-down of the gene targets.

Several other mechanisms also regulate cholesterol synthesis (Fig. 21-44). Hormonal control is mediated by covalent modification of HMG-CoA reductase itself. The enzyme exists in phosphorylated (inactive) and dephosphorylated (active) forms. Glucagon stimulates phosphorylation (inactivation), and insulin promotes dephosphorylation, activating the enzyme and favoring cholesterol synthesis. High intracellular concentrations of cholesterol activate ACAT, which increases esterifi-cation of cholesterol for storage. Finally, a high cellular cholesterol level diminishes transcription of the gene that encodes the LDL receptor, reducing production of the receptor and thus the uptake of cholesterol from the blood.

Acetyl-CoA multistep

^-Hydroxy-/3-methyl-glutaryl-CoA

HMG-CoA reductase

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