Inhibition of Squalene Synthase but Not Squalene Cyclase Prevents Mevalonate-Mediated Suppression of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Synthesis at a Posttranscriptional Level

Peffley, Dennis M.; Gayen, Apurba K.

doi:10.1006/abbi.1996.9796

Cited by 20 publications

(31 citation statements)

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“…Thus, a reasonable model would be that the pathway product FPP, the substrate of squalene synthase, was a source of the regulatory signal that controlled UBC7-dependent Hmg2p ubiquitination and degradation. Similar degradation-enhancing effects of ZA on mammalian HMG-R have been reported both in cultured cells and in vivo in rat liver (9,24). Furthermore, the molecule farnesol, derived from FPP, has been posited to be a signal for HMG-R degradation in mammals (25,26).…”

Section: Resultsmentioning

confidence: 55%

Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase

Hampton

Bhakta

1997

Proc. Natl. Acad. Sci. U.S.A.

138

144

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Regulation of the sterol-synthesizing mevalonate pathway occurs in part through feedback-regulated endoplasmic reticulum degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R). In yeast, the Hmg2p isozyme of HMG-R is regulated in this manner. We have tested the involvement of ubiquitination in the regulated degradation of Hmg2p, by using both genetic and direct biochemical approaches. Hmg2p degradation required the UBC7 gene, and Hmg2p protein was directly ubiquitinated. Hmg2p ubiquitination was dependent on UBC7 and was specific for the degraded yeast Hmg2p isozyme. Furthermore, Hmg2p ubiquitination was regulated by the mevalonate pathway in a manner consistent with regulation of Hmg2p stability. Thus, regulated ubiquitination appeared to be the mechanism by which Hmg2p stability is controlled in yeast. Finally, our data indicated that the feedback signal controlling Hmg2p ubiquitination and degradation was derived from farnesyl diphosphate, and thus implied conservation of an HMG-R degradation signal between yeast and mammals.

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Section: Resultsmentioning

confidence: 55%

Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase

Hampton

Bhakta

1997

Proc. Natl. Acad. Sci. U.S.A.

138

144

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“…The existence of such oxysterol signals has been proposed from the observations that HMGR degradation is enhanced as a result of either 24,25-oxidolanosterol or 25-hydroxycholesterol addition to cells (2,3,(21)(22)(23)(24)(25) or when endogenous oxysterols are increased by inhibition of oxidosqualene-lanosterol cyclase (34). It appears that oxysterols do not alter HMGR degradation alone, but require the presence of a non-sterol positive signal derived from FPP to enhance HMGR degradation (20).…”

Section: Resultsmentioning

confidence: 99%

An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast

Gardner

Shan²,

Matsuda

et al. 2001

Journal of Biological Chemistry

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Sterol synthesis by the mevalonate pathway is modulated, in part, through feedback-regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). In mammals, both a non-sterol isoprenoid signal derived from farnesyl diphosphate (FPP) and a sterol-derived signal appear to act together to positively regulate the rate of HMGR degradation. Although the nature and number of sterol-derived signals are not clear, there is growing evidence that oxysterols can serve in this capacity. In yeast, a similar non-sterol isoprenoid signal generated from FPP acts to positively regulate HMGR degradation, but the existence of any sterol-derived signal has thus far not been revealed. We now demonstrate, through the use of genetic and pharmacological manipulation of oxidosqualene-lanosterol cyclase, that an oxysterol-derived signal positively regulated HMGR degradation in yeast. The oxysterol-derived signal acted by specifically modulating HMGR stability, not endoplasmic reticulum-associated degradation in general. Direct biochemical labeling of mevalonate pathway products confirmed that oxysterols were produced endogenously in yeast and that their levels varied appropriately in response to genetic or pharmacological manipulations that altered HMGR stability. Genetic manipulation of oxidosqualene-lanosterol cyclase did result in the buildup of detectable levels of 24,25-oxidolanosterol by gas chromatography, gas chromatography-mass spectroscopy, and NMR analyses, whereas no detectable amounts were observed in wild-type cells or cells with squalene epoxidase down-regulated. In contrast to mammalian cells, the yeast oxysterol-derived signal was not required for HMGR degradation in yeast. Rather, the function of this second signal was to enhance the ability of the FPP-derived signal to promote HMGR degradation. Thus, although differences do exist, both yeast and mammalian cells employ a similar strategy of multiinput regulation of HMGR degradation.

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“…We therefore designed experiments to clarify whether the inhibition of sterol or nonsterol derivatives originating from the biotransformation of mevalonate is important in controlling inflammation (Figure 1). We used lovastatin, pravastatin, and simvastatin as inhibitors of the synthesis of sterol and nonsterol intermediates 13,21,22 and squalestatin as a selective inhibitor of the synthesis of sterol derivatives only [23][24][25] (Figure 1). We eval-uated the anti-inflammatory effect of these molecules using the in vivo air-pouch model of local inflammation 26,27 and measuring leukocyte migration and chemotactic cytokine production.…”

Section: See P 1256mentioning

confidence: 99%

In Vivo Anti-Inflammatory Effect of Statins Is Mediated by Nonsterol Mevalonate Products

Diomede

Albani

Sottocorno

et al. 2001

ATVB

205

112

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Abstract-This study set out to clarify whether the inhibition of sterol or nonsterol derivatives arising from mevalonate biotransformation plays a major role in the in vivo anti-inflammatory action of statins. Hepatic synthesis of all these derivatives was inhibited in mice by administered statins, whereas squalestatin inhibited only sterol derivatives. Using a short-term treatment schedule, we found that statins reduced the hepatic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase without affecting blood cholesterol. This treatment inhibited lipopolysaccharide-and carrageenan-induced pouch leukocyte recruitment and the exudate production of interleukin-6, monocyte chemotactic protein-1, and RANTES. Coadministration of mevalonate reversed the effect of statin on leukocyte recruitment. The inhibition of sterol synthesis by squalestatin did not have any anti-inflammatory effect, indicating that the biosynthesis of nonsterol compounds arising from mevalonate is crucial for the in vivo regulation of cytokine and chemokine production by statins.

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Inhibition of Squalene Synthase but Not Squalene Cyclase Prevents Mevalonate-Mediated Suppression of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Synthesis at a Posttranscriptional Level

Cited by 20 publications

References 0 publications

Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase

Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase

An Oxysterol-derived Positive Signal for 3-Hydroxy- 3-methylglutaryl-CoA Reductase Degradation in Yeast

In Vivo Anti-Inflammatory Effect of Statins Is Mediated by Nonsterol Mevalonate Products

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