Post-transcriptional Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme-A Reductase by Mevalonate

Straka, M S; Panini, S R

doi:10.1006/abbi.1995.1158

Cited by 14 publications

(11 citation statements)

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“…39 and 40). Hydroxymethylglutaryl-CoA reductase, the rate-limiting enzyme for cholesterol synthesis, is another example of posttranscriptional regulation (41)(42)(43)(44)(45)(46). In addition to transcriptional suppression by sterols, this enzyme is further regulated by mevalonate through a posttranscriptional mechanism, primarily by accelerating the degradation of this protein (41,44,45).…”

Section: Discussionmentioning

confidence: 99%

Posttranscriptional Control of the Expression and Function of Diacylglycerol Acyltransferase-1 in Mouse Adipocytes

Yu¹,

Zhang²,

Oelkers³

et al. 2002

Journal of Biological Chemistry

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Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) catalyzes the final step of triglyceride synthesis in mammalian cells. Data obtained from DGAT1-knockout mice have indicated that this enzyme plays an important role in energy homeostasis. We investigated the regulation of the expression and function of DGAT1 in mouse 3T3-L1 cell as a model for mammalian adipocytes. We demonstrated that the DGAT1 protein level increased by ϳ90-fold following differentiation of 3T3-L1 into mature adipocytes, a change that was accompanied by ϳ7-fold increase in DGAT1 mRNA. On the other hand, forced overexpression of DGAT1 mRNA by >20-fold via a recombinant adenovirus only resulted in ϳ2-fold increase in DGAT1 protein in mature adipocytes and little increase in preadipocytes. These results indicated that gene expression of DGAT1 in adipocytes is subjected to rigorous posttranscriptional regulation, which is modulated significantly by the differentiation status of 3T3-L1 cells. Protein stability is not a significant factor in the control of DGAT1 expression. The steady-state levels of DGAT1 were unaffected by blockage of proteolytic pathways by ALLN. However, translational control was suggested by sequence analysis of the 5-untranslated region of human DGAT1 (hDGAT1) mRNA. We found that the level of DGAT1 activity was predominantly a function of the steady-state level of DGAT1 protein. No significant functional changes were observed when the conserved tyrosine phosphorylation site in hDGAT1 was mutated by a single base pair substitution. Despite only a ϳ2-fold increase in DGAT1 protein caused by recombinant viral transduction, a proportionate increase in cellular triglyceride synthesis resulted without affecting the triglyceride lipolysis rate, leading to >2-fold increase in intracellular triglyceride accumulation. No change in adipocyte morphology or in the expression levels of lipoprotein lipase, proxisomal proliferation-activating receptor-␥, and aP2 was evident secondary to DGAT1 overexpression at different stages in 3T3-L1 differentiation. These data suggest that dysregulation of DGAT1 may play a role in the development of obesity, and manipulation of the steady-state level of DGAT1 protein may offer a potential means to treat or prevent obesity. Adiposity, or the amount of triglyceride (TG)1 stored in adipocytes, is fundamentally a net result of two opposing metabolic processes, i.e. lipogenesis and lipolysis. These are highly regulated processes influenced by various hormones, cytokines, nutrients, and other factors (see Ref. 1) that may either serve as substrates or function as signaling molecules for one or more specific metabolic pathways. Acyl-CoA:diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is thought to be a key enzyme in controlling the synthetic rate of TG in adipocytes (2). It catalyzes the last step in the de novo TG synthetic pathway employed by various types of cells, producing TG from its two substrates, diacylglycerol and fatty acyl-CoA (for a review, see Refs. 3 and 4). Two DGAT genes have been identified....

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Section: Discussionmentioning

confidence: 99%

Posttranscriptional Control of the Expression and Function of Diacylglycerol Acyltransferase-1 in Mouse Adipocytes

Yu¹,

Zhang²,

Oelkers³

et al. 2002

Journal of Biological Chemistry

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“…Although it is generally well accepted that the sterol component cannot cause accelerated degradation without the nonsterol component (14,15), previous reports have disagreed whether the nonsterol component reciprocally requires the sterol component. Our group (15) and others (8) have reported that the sterol product is not required, citing that inhibitors within the sterol branch of the isoprenoid pathway do not prevent a mevalonate-induced response. On the contrary, Correll and Edwards (16) have found that inhibitors in the sterol branch do block the effect of mevalonate, suggesting that the sterol component is required.…”

Section: Effect Of Farnesol On Degradation Of Hmg-coa Reductase Inmentioning

confidence: 97%

Regulation of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Degradation by the Nonsterol Mevalonate Metabolite Farnesol in Vivo

Meigs¹,

Roseman

Simoni

1996

Journal of Biological Chemistry

138

103

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We have previously reported that degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in the isoprenoid pathway leading to cholesterol production, can be accelerated in cultured cells by the addition of farnesyl compounds, which are thought to mimic a natural, nonsterol mevalonate metabolite(s). In this paper we report accelerated reductase degradation by the addition of farnesol, a natural product of mevalonate metabolism, to intact cells. We demonstrate that this regulation is physiologically meaningful, shown by its blockage by several inhibitory conditions that are known to block the degradation induced by mevalonate addition. We further show that intracellular farnesol levels increase significantly after mevalonate addition. Based on these results, we conclude that farnesol is a nonsterol, mevalonate-derived product that plays a role in accelerated reductase degradation. Our conclusion is in agreement with a previous report (Correll, C. C., Ng, L., and Edwards, P. A. (1994) J. Biol. Chem. 269, 17390-17393), in which an in vitro system was used to study the effect of farnesol on reductase degradation. However, the apparent stimulation of degradation in vitro appears to be due to nonphysiological processes. Our findings demonstrate that in vitro, farnesol causes reductase to become detergent insoluble and thus lost from immunoprecipitation experiments, yielding apparent degradation. We further show that another resident endoplasmic reticulum protein, calnexin, similarly gives the appearance of protein degradation after farnesol addition in vitro. However, after the addition of farnesol to cells in vivo, calnexin remains stable, whereas reductase is degraded, providing further evidence that the in vivo effects of farnesol are physiologically meaningful and specific for reductase, whereas the in vitro effects are not.

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“…Depletion of mevalonate is known to alter the expression of key proteins involved in isoprene metabolism, most notably HMG-CoA reductase. The level of HMG-CoA reductase is under multivalent control at both transcriptional and post-transcriptional sites, and this regulation is dependent on both sterol and non-sterol components of the cholesterol biosynthetic pathway (17)(18)(19)(20). We and others have used statins as a tool to impair protein prenylation because depletion of mevalonate results in depletion of farnesyl pyrophosphate and geranylgeranyl pyrophosphate (21)(22)(23).…”

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confidence: 99%

Consequences of Mevalonate Depletion

Holstein

Wohlford‐Lenane

Hohl

2002

Journal of Biological Chemistry

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Post-transcriptional Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme-A Reductase by Mevalonate

Cited by 14 publications

References 0 publications

Posttranscriptional Control of the Expression and Function of Diacylglycerol Acyltransferase-1 in Mouse Adipocytes

Posttranscriptional Control of the Expression and Function of Diacylglycerol Acyltransferase-1 in Mouse Adipocytes

Regulation of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Degradation by the Nonsterol Mevalonate Metabolite Farnesol in Vivo

Consequences of Mevalonate Depletion

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