Disease relevance of HMGCR

• The results show that HMG-CoA reductase inhibitors reverse the down-regulatory effect of cyclosporine on LDL receptor activity, thus further supporting our previous findings and also providing a rationale for the already established treatment in cyclosporine-induced hypercholesterolemia with HMG-CoA reductase inhibitors [1].
• Effects of compactin, mevalonate and low-density lipoprotein on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and low-density-lipoprotein-receptor activity in the human hepatoma cell line Hep G2 [2].
• Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549 [3].
• Low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA levels are coordinately reduced in human renal cell carcinoma [4].
• Here we analyzed the 8302A/C and the (TTA)n polymorphisms in the HMGCR gene in 169 Chinese patients with coronary heart disease (CHD) and 161 age-matched controls [5].

Psychiatry related information on HMGCR

• As statins strike at several parts of the Alzheimer's disease mechanism (such as the infliction of cholesterol-dependent cerebrovascular damage) by inhibiting HMG-CoA reductase, their long-term use (starting as early as possible during Alzheimer's disease development) should slow or even prevent the progression of Alzheimer's disease [6].
• Several modalities that upregulate eNOS expression and/or activity have recently been identified, including HMG-CoA reductase inhibitors (statins), steroid hormones, nutrients and physical activity [7].
• Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83) [8].
• However, the emergence of powerful new agents with LDL cholesterol-lowering and HDL-cholesterol-increasing effects (HMG CoA reductase inhibitors), characterized by excellent patient compliance, suggests that drug therapy may be useful for selected elderly patients [9].
• The pleiotropic effects of HMG-CoA reductase inhibitors: their role in osteoporosis and dementia [10].

High impact information on HMGCR

• CONCLUSIONS: The extent to which the volume of atherosclerotic plaque decreased, stabilized, or increased was directly related to treatment with HMG-CoA reductase inhibitors and the resulting serum LDL cholesterol levels [11].
• Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography [11].
• SCAP has multiple membrane-spanning regions, five of which resemble the sterol-sensing domain of HMG CoA reductase, an endoplasmic reticulum enzyme whose degradation is accelerated by sterols [12].
• Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients) [13].
• We hypothesized that cholesterol-lowering therapy with the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin could improve endothelium-mediated responses in patients with coronary atherosclerosis [14].

Chemical compound and disease context of HMGCR

• For this purpose we determined low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) transcript levels and total tissue cholesterol in both tumors and normal kidney tissue in a series of samples from 29 patients with renal cell carcinoma [4].
• The present study evaluated the effect of gemfibrozil on the LDL receptor in human hepatoma cells compared with that of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase [15].
• In a cultured human hepatoblastoma cell line, Hep G2, chenodeoxycholic acid (CDCA) induced LDL receptor mRNA levels approximately 4 fold and mRNA levels for HMG-CoA reductase and HMG-CoA synthase two fold [16].
• BACKGROUND: We evaluated the HMGCoA reductase activity and LDL receptor levels in human colon cancer as well as the effects of simvastatin on in vitro cell growth and apoptosis of DLD-1 and Caco2 cell lines [17].
• Although the efficacy of fluvastatin (HMG-CoA reductase inhibitor) in the treatment of primary hypercholesterolemia is well documented, a wide interindividual variation treatment response has been observed [18].

Biological context of HMGCR

• We have assigned the HMG-CoA reductase gene, HMGCR, to chromosome 5 by Southern blotting of DNA from a somatic cell hybrid panel and to bands 5q13.3-q14 by in situ hybridizations of the cDNA probe to human metaphase cells with normal and rearranged chromosomes [19].
• A full length cDNA for human 3-hydroxy-3-methylglutaryl coenzyme A reductase, the membrane-bound glycoprotein that regulates cholesterol synthesis, was isolated from a human fetal adrenal cDNA library [20].
• HMG-CoA reductase catalyzes the synthesis of mevalonate, a crucial intermediate in the biosynthesis of cholesterol and non-sterol isoprenoid compounds essential for cell growth [3].
• The results of the present study, obtained by one-step RT-PCR assay, demonstrated that both SOD1 and the metal-free form of enzyme (Apo SOD1) inhibit HMG-CoA reductase gene expression in hepatocarcinoma HepG2 cells, in normal human fibroblasts, and in fibroblasts of subjects affected by familiar hypercholesterolemia [21].
• Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens [22].

Anatomical context of HMGCR

• We measured HMG CoA reductase protein concentration and microsomal enzyme activity in freshly isolated mononuclear leukocytes from normal individuals and patients with heterozygous or homozygous familial hypercholesterolemia (FH) [23].
• METHODS: Skin fibroblasts from MK-deficient patients and from controls were cultured for 7 days with either simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or zaragozic acid A, an inhibitor of squalene synthase [24].
• We show that the HMG-CoA reductase in A549 cell line was subject to a multivalent feedback control [3].
• In conclusion, inhibition of HMG-CoA reductase in endothelial cells attenuates VCAM-1 expression, but increases E-selectin expression, after cytokine induction [25].
• The HMG-CoA reductase activity of the A549 tumor cell line is higher than that of normal human fibroblasts [3].

Associations of HMGCR with chemical compounds

• Sterols accelerate degradation of the ER enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), which catalyzes a rate-controlling step in cholesterol biosynthesis [26].
• Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain [26].
• The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men [27].
• Phosphopeptide mapping of native, 100 kd microsomal HMG-CoA reductase confirms that this C-terminal serine is the only major site phosphorylated in the intact enzyme by the AMP-activated protein kinase [28].
• In this study, in HepG2 cells, we investigated the effects of HMG-CoA reductase inhibitors on cellular LDL catabolism in the presence of cyclosporine [1].
• Individuals heterozygous for the G allele of rs17238540 in the HMGCR gene may respond less well to statin therapy in terms of total cholesterol and triglyceride lowering [29].

Physical interactions of HMGCR

• 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the binding activity and nuclear level of Oct-1 in mononuclear cells [30].
• Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG-CoA reductase inhibition and other pharmacologic properties [31].
• Therefore, antioxidant and endothelium-stabilising properties of HMG-CoA reductase inhibitors may contribute in reducing the risk of stroke in recipients [32].

Enzymatic interactions of HMGCR

• Purified cathepsin L also efficiently cleaved HMG-CoA reductase in isolated ER preparations [33].

Regulatory relationships of HMGCR

• Decreased HMG CoA reductase activity and catalytic efficiency in mononuclear leukocytes and perhaps other cells in FH may represent a fundamental abnormality in the regulation of this enzyme independent of that induced by the LDL-receptor defect and may provide new insight into the control of cholesterol metabolism in FH [23].
• In addition, only treatment with t10c12-CLA markedly induced mRNA expression of SREBP-2 and HMG-CoA reductase and slightly induced that of SREBP-1 (P<0.05) [34].
• Substantial evidence has demonstrated that the cytosolic antioxidant enzyme CuZn superoxide dismutase (SOD1) inhibits the HMG-CoA reductase activity in rat hepatocytes and in human fibroblasts by decreasing cholesterol synthesis [21].
• Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase [35].
• Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis [36].

Other interactions of HMGCR

• Here, we show that degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1 [26].
• Insig-1 appears to play an essential role in the sterol-mediated trafficking of two proteins with sterol-sensing domains, HMG CoA reductase and SCAP [26].
• To characterize the coordinate regulation of cholesterol metabolism in human liver, we simultaneously quantified mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), and low- density lipoprotein receptors (LDLRs) in liver biopsies from 76 patients undergoing cholecystectomy [37].
• Each also caused significant HMGCR increments and SR-B1 decrements and left ABCA1 intact [38].
• Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect [39].

Analytical, diagnostic and therapeutic context of HMGCR

• The expression of LDL-R and HMG CoA reductase was also investigated using real time PCR [40].
• METHODS AND RESULTS: Screening human umbilical vein endothelial cells (HUVECs) with complementary DNA microarray for the gene expression modified by homocysteine (Hcy) revealed that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was upregulated [41].
• Provided patients who had received total parenteral nutrition preoperatively were excluded from analysis, a significant correlation was also observed between length of resected ileum and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity [42].
• A single-blind study with fluvastatin, an HMG-CoA reductase inhibitor, was conducted in 64 familial hypercholesterolemia patients who had defined apolipoprotein E (apo E) and apolipoprotein(a) [apo(a)] isoforms [43].
• Western blot analysis indicated that the amount of HMG-CoA reductase protein rapidly decreased in the presence of SR-12813 [44].

References