Disease relevance of Hmgcr

• During the ageing process in rats hypercholesterolemia occurs in concert with full activation, lowered degradation rate and an unchanged level of the rate limiting cholesterol biosynthesis enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) [1].
• Contribution of increased HMG-CoA reductase gene expression to hypercholesterolemia in experimental chronic renal failure [2].
• We optimized an immunoblot procedure for quantifying small amounts of both the native and the soluble forms of HMG-CoA reductase from Reuber H35 hepatoma cells [3].
• In contrast to inhibition, up-regulation of hepatic HMG-CoA synthase activities by cholestyramine, bile fistula, and lovastatin was much less than HMG-CoA reductase activities [4].
• Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in Morris hepatoma 7800 after intravenous injection of mevalonic acid [5].

Psychiatry related information on Hmgcr

• Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease [6].
• Dietary modification of the distribution of 3-hydroxy-3-methylglutaryl coenzyme A reductase and sterol synthesizing activities in the rat small intestine [7].
• The semi-purified diet used here resulted in consistently lower levels of HMG-CoA reductase activity than the commercial diet regardless of feeding pattern [8].

High impact information on Hmgcr

• Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. 1976 [9].
• In hypophysectomized (Hx) rats, the activities of the rate-limiting enzymes in cholesterol and bile acid biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and cholesterol 7alpha-hydroxylase (C7alphaOH), were reduced by 71 and 64%, respectively [10].
• Hepatic microsomal cholesterol was increased and the enzymatic activities of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in hepatic microsomes were reduced [11].
• Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types [12].
• Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h [13].

Chemical compound and disease context of Hmgcr

• The effect of i.v. injection of mevalonate on the activity of microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was studied in livers from non-tumor-bearing rats and in host liver and hepatomas from rats bearing transplantable Morris hepatoma 7800 [5].
• The mechanism of action of serum lipoproteins and 25-hydroxycholesterol on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in hepatoma tissue culture (HTC) cells was investigated using antiserum against purified rat liver HMG-CoA reductase (Heller, R. A., and Shrewsbury, M. A. (1976)J. Biol. Chem. 251, 3815-3822) [14].
• OBJECTIVES: We examined the effects of early treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on the progression of glucose intolerance and cardiovascular remodeling in a model of spontaneously developing type II diabetes mellitus (DM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rats [15].
• H4-II-E-C3 hepatoma cells in culture respond to lipid-depleted media and to mevinolin with increased sterol synthesis from [14C]acetate and rise of 3-hydroxy-3-methylglutaryl coenzyme A reductase levels [16].
• CONCLUSION: The combination of an angiotensin antagonist with an HMG-CoA reductase inhibitor confers superiority over monotherapies on renal function, as assessed by prevention of albuminuria and rise in plasma BUN and creatinine [17].

Biological context of Hmgcr

• Farnesol and geraniol chemopreventive activities during the initial phases of hepatocarcinogenesis involve similar actions on cell proliferation and DNA damage, but distinct actions on apoptosis, plasma cholesterol and HMGCoA reductase [18].
• Phosphorylation and inactivation of HMG-CoA reductase at the AMP-activated protein kinase site in response to fructose treatment of isolated rat hepatocytes [19].
• The results also indicate that the physiological diurnal rhythm of HMG-CoA reductase activity is preserved in the course of experimental CRF [2].
• In the liver, cholesterol homeostasis is strictly regulated through the modulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis [20].
• In contrast, the downregulation of HMG-CoA reductase caused by eicosapentaenoic acid is not due to decreased protein synthesis, since similar levels of protein were found in the presence and absence of this fatty acid [3].

Anatomical context of Hmgcr

• This supports previous data that suggest that dietary or luminal cholesterol affects both HMG-CoA reductase and ACAT activity in the small intestine [21].
• Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum [22].
• This study is a quantitative biochemical and immunoelectron microscopical analysis of HMG-CoA reductase in rat liver peroxisomes and microsomes of normal and cholestyramine-treated animals [23].
• We show that the sequence Arg224 through Leu242 of HMG-CoA reductase (peptide G) faces the cytoplasm both in cultured cells and in rat liver, whereas the sequence Thr284 through Glu302 (peptide H) faces the lumen of the ER [22].
• A procedure for the purification of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating); EC 1.1.1.34] solubilized from rat liver microsomes is reported [24].

Associations of Hmgcr with chemical compounds

• A rice bran oil diet increases LDL-receptor and HMG-CoA reductase mRNA expressions and insulin sensitivity in rats with streptozotocin/nicotinamide-induced type 2 diabetes [25].
• However, dietary levan did not affect the gene expression of hepatic malic enzyme, phosphatidate phosphohydrolase and HMG CoA reductase [26].
• Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16% [13].
• The data suggest that intestinal HMG-CoA reductase and ACAT activities are regulated by plasma lipoproteins independently of luminal factors [21].
• Administration of progesterone, an inhibitor of ACAT, had no effect on HMG CoA reductase and increased biliary cholesterol output 32% at 1 h [13].

Physical interactions of Hmgcr

• HMG-CoA reductase inhibitors are known to modulate some cellular signal transduction systems by blocking the membrane attachment of low molecular weight GTP binding proteins such as p21ras [27].

Regulatory relationships of Hmgcr

• Taken together, these results indicate that insulin and glucagon regulate HMG-CoA reductase gene expression largely at the level of enzyme protein through changes in mRNA concentrations [28].
• It is therefore conceivable that taurocholate may suppress cholesterol 7 alpha-hydroxylase primarily by down-regulating the activity of HMG-CoA reductase [29].
• 2. When added individually, nerve growth factor (NGF), basic fibroblast growth factor, and epidermal growth factor induce an increase in HMG-CoA reductase activity in cells grown in serum-containing medium [30].
• HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells [31].

Other interactions of Hmgcr

• Modified HMG-CoA reductase and LDLr regulation is deeply involved in age-related hypercholesterolemia [1].
• Using immunoprecipitation from the microsomal fraction of 32P-labelled cells, we also show that this treatment leads to a 2.6-fold increase in the phosphorylation of the 100 kDa subunit of HMG-CoA reductase [19].
• In contrast, SREBP-2 was present in rat liver nuclei, and its target gene, HMG-CoA reductase, was expressed above adult levels prior to weaning [32].
• Moreover, an inhibitor of HMG-CoA reductase, pravastatin, reduced cyclin E expression and Cdk2 activation and caused G1 arrest in the astrocytes [33].
• The lard-fish oil diet prevented hepatic triglyceride accumulation and decreased FAS activity and mass by 3.5-fold (P < 0.001) but did not further decrease HMG-CoA reductase activity [34].

Analytical, diagnostic and therapeutic context of Hmgcr

• The effect of perfusion of an isolated rat liver on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase was studied [35].
• Immunoelectron labeling of ultrathin frozen sections of normal liver, using two monoclonal antibodies to purified rat liver microsomal HMG-CoA reductase, indicated that the enzyme is present in the matrix of peroxisomes [23].
• This induction of HMG-CoA reductase immunofluorescence was centered periportally [36].
• Data are also presented that indicate the separation of enzymatically active and inactive species of 3-hydroxy-3-methylglutaryl-coenzyme A reductase on affinity chromatography on a coenzyme A column [24].
• We determined the subcellular distribution of HMG-CoA reductase at high resolution by means of immunoelectron microscopy on ultrathin frozen liver sections of rats treated with lovastatin and cholestyramine [37].

References