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Review Article

Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase

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Pages 185-198 | Received 27 Jan 2010, Accepted 12 Apr 2010, Published online: 20 May 2010
 

Abstract

Multiple mechanisms for feedback control of cholesterol synthesis converge on the rate-limiting enzyme in the pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase. This complex feedback regulatory system is mediated by sterol and nonsterol metabolites of mevalonate, the immediate product of reductase activity. One mechanism for feedback control of reductase involves rapid degradation of the enzyme from membranes of the endoplasmic reticulum (ER). This degradation results from the accumulation of sterols in ER membranes, which triggers binding of reductase to ER membrane proteins called Insig-1 and Insig-2. Insig binding leads to the recruitment of a membrane-associated ubiquitin ligase called gp78 that initiates ubiquitination of reductase. Ubiquitinated reductase then becomes extracted from ER membranes and is delivered to cytosolic 26S proteasomes through an unknown mechanism that is mediated by the gp78-associated ATPase Valosin-containing protein/p97 and appears to be augmented by nonsterol isoprenoids. Here, we will highlight several advances that have led to the current view of mechanisms for sterol-accelerated, ER-associated degradation of reductase. In addition, we will discuss potential mechanisms for other aspects of the pathway such as selection of reductase for gp78-mediated ubiquitination, extraction of the ubiquitinated enzyme from ER membranes, and the contribution of Insig-mediated degradation to overall regulation of reductase in whole animals.

Acknowledgements

We thank Drs. Jin Ye and Isamu Hartman for critical reading of this manuscript.

Declaration of interest

Work in the DeBose-Boyd laboratory is supported by grants from the National Institute of Health (HL20948) and the Perot Family Foundation. R.D.-B. is an Early Career Scientist of the Howard Hughes Medical Institute, an Established Investigator of the American Heart Association, and a W.M. Keck Foundation Distinguished Young Scholar in Medical Research. The authors declare no conflict of interest.

Editor: Michael M. Cox

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