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, 281 (35), 25054-61

Insig-dependent Ubiquitination and Degradation of 3-hydroxy-3-methylglutaryl Coenzyme a Reductase Stimulated by Delta- And Gamma-Tocotrienols

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Insig-dependent Ubiquitination and Degradation of 3-hydroxy-3-methylglutaryl Coenzyme a Reductase Stimulated by Delta- And Gamma-Tocotrienols

Bao-Liang Song et al. J Biol Chem.

Abstract

Sterol-regulated ubiquitination marks 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-determining enzyme in cholesterol synthesis, for endoplasmic reticulum (ER)-associated degradation by 26 S proteasomes. This degradation, which results from sterol-induced binding of reductase to ER membrane proteins called Insigs, contributes to the complex, multivalent feedback regulation of the enzyme. Degradation of HMG-CoA reductase is also stimulated by various forms of vitamin E, a generic term for alpha-, beta-, delta-, and gamma-tocopherols and tocotrienols, which are primarily recognized for their potent antioxidant activity. Here, we show that delta-tocotrienol stimulates ubiquitination and degradation of reductase and blocks processing of sterol regulatory element-binding proteins (SREBPs), another sterol-mediated action of Insigs. The gamma-tocotrienol analog is more selective in enhancing reductase ubiquitination and degradation than blocking SREBP processing. Other forms of vitamin E neither accelerate reductase degradation nor block SREBP processing. In vitro assays indicate that gamma- and delta-tocotrienol trigger reductase ubiquitination directly and do not require further metabolism for activity. Taken together, these results provide a biochemical mechanism for the hypocholesterolemic effects of vitamin E that have been observed in animals and humans.

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