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Review
. 2013 Jun 28;288(26):18707-15.
doi: 10.1074/jbc.R113.479808. Epub 2013 May 21.

Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)

Laura J Sharpe  1 , Andrew J Brown
Affiliations
Review

Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)

Laura J Sharpe et al. J Biol Chem. .

Abstract

3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control.

Keywords: Cholesterol; Cholesterol Regulation; ER-associated Degradation; NSDHL; Post-translational Modification; SREBP; Squalene Monooxygenase; Sterol.

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Figures

FIGURE 1.
FIGURE 1.
Cholesterol synthesis pathway. The mevalonate pathway leads to lanosterol, which can then be diverted into either the Bloch pathway, producing cholesterol via desmosterol, or the Kandutsch-Russell pathway, via 7-dehydrocholesterol. Two other branches also diverge from the mevalonate pathway. Isoprenoids are produced by geranylgeranyl-diphosphate synthase (GGPPS) acting twice to convert farnesyl diphosphate to geranylgeranyl diphosphate, and flux through the shunt pathway occurs when SM acts twice to convert squalene 2,3-epoxide into diepoxysqualene, eventually leading to the production of 24(S),25-epoxycholesterol. Intermediates and enzymes in this shunt pathway are not yet fully elucidated (75) but are presumed to follow the Kandutsch-Russell pathway. MK, mevalonate kinase; PMK, phosphomevalonate kinase; MVD, diphosphomevalonate decarboxylase; FPPS, farnesyl-pyrophosphate synthase; SQS, squalene synthase; LDM, lanosterol 14α-demethylase; SC5D, sterol C5-desaturase.
FIGURE 2.
FIGURE 2.
SRE consensus sequences. SREs from either seven cholesterol synthesis genes (A) or 11 other non-cholesterogenic SREBP targets (B) were used to create a consensus sequence with WebLogo 3.3. This figure was modified from Ref. .
See this image and copyright information in PMC

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