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Membrane-mediated control of hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase.

ABSTRACT: Previously we [Sabine & James (1976) Life Sci. 18, 1185--1192] proposed that 'the activity of hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase is critically regulated by the fluidity of its supporting microsomal membrane'. In the present work we examined further this concept of membrane-mediated control, with respect to the specific hypothesis that such control might function as a common mechanism both for the co-ordinated regulation of other enzymes affected by cholesterol feeding and also for the subcellular integration of the several physiological factors known to influence this enzyme's activity. Contrary to earlier expectations, this hypothesis now appears not to hold. We report here that, under those conditions of short-term cholesterol feeding that affected the reductase, a variety of other microsomal enzymes did not display membrane-function interactions, i.e. neither enzymes involved in cholesterol metabolism and also affected by cholesterol feeding (cholesterol 7 alpha-hydroxylase), nor those involved in cholesterol metabolism and not affected by cholesterol feeding (hydroxymethylglutaryl-CoA hydrolase, acyl-CoA:cholesterol acyltransferase), nor those not directly involved in cholesterol metabolism at all (glucose 6-phosphatase). Furthermore, we observed no evidence for the operation of membrane-mediated control of the reductase in other situations known to influence its activity, i.e. starvation, diurnal rhythm, the very early stages of cholesterol feeding and various manipulations in vitro.

SUBMITTER: Sipat AB

PROVIDER: S-EPMC1162825 | biostudies-other | 1981 Mar

REPOSITORIES: biostudies-other

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Project description:ObjectiveIn addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis.MethodsThe effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy.ResultsStatin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR.ConclusionStatins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.

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Membrane-mediated control of hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase.

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