Disease relevance of Hmgcr

• The P-407-induced hypercholesterolemia was accounted for by increased activity and protein expression of HMG-CoA reductase [1].
• Renal HMGCR mRNA did not fall despite sepsis triggered cholesterol loading, indicating a failure of negative feedback activity [2].
• Lipid-lowering drugs in the MPTP mouse model of Parkinson's disease: Fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not [3].
• 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome [4].
• We demonstrate expression and coordinate induction of PPARgamma and lipogenic enzymes (HMG-CoA synthase, HMG-CoA reductase and fatty acid synthase) in a murine lung alveolar carcinoma cell line (Line 1) treated with the PPARgamma agonist troglitazone (TRO) [0-100 microM] [5].

Psychiatry related information on Hmgcr

• Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation [6].
• HMG-CoA reductase inhibitors (statins) in the treatment of Alzheimer's disease and why it would be ill-advise to use one that crosses the blood-brain barrier [7].

High impact information on Hmgcr

• The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease [8].
• Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells [8].
• Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase [9].
• Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates [10].
• Orally administered cholesterol-lowering HMG-CoA reductase inhibitors (known as statins), which exhibit immunomodulatory properties and are effective in treatment of the MS model EAE, are being tested in MS [11].

Chemical compound and disease context of Hmgcr

• Inhibition of vascular Rho guanosine-5'-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion [12].
• We examined the effects of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on human pancreatic cancer cell invasion in vitro and experimental liver metastasis in vivo [13].
• In contrast, thioglycolate-elicited macrophages from control mice with diet-induced hypertriglyceridemia had normal levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity [14].
• The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis [15].
• Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2 [16].

Biological context of Hmgcr

• We have now mapped the mouse gene Hmgcr to mouse chromosome 13 by Southern analysis of somatic cell hybrids [17].
• Hypercholesterolemia was associated with an up-regulation of both the protein expression and activity of HMG-CoA reductase and decreased LDLr expression [1].
• Although it has been postulated that a second, peroxisome-specific HMG-CoA reductase could substitute for the ER reductase in vitro, we speculate that the putative peroxisomal reductase gene, if existed, does not fully compensate for the lack of the ER enzyme at least in embryogenesis [18].
• Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression [19].
• This line, designated CR200, expressed a stable phenotype of a greater than 100-fold higher resistance to the inhibitor and a 160-fold higher HMG-CoA reductase activity than did the parental FM3A cell line when grown in the presence of low-density lipoprotein (LDL) [20].

Anatomical context of Hmgcr

• In contrast, the embryos homozygous for the Hmgcr mutant allele were recovered at the blastocyst stage, but not at E8.5, indicating that HMG-CoA reductase is crucial for early development of the mouse embryos [18].
• Oil Red O staining revealed that PPARgamma2 induces lipid accumulation in hepatocytes [21].
• Overaccumulation of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase in a compactin(ML-236B)-resistant mouse cell line with defects in the regulation of its activity [20].
• Purification of brain peroxisomes and localization of 3-hydroxy-3-methylglutaryl coenzyme A reductase [22].
• Our results indicate that the HMG-CoA reductase inhibitors fluvastatin and simvastatin reduce, in a concentration-dependent manner, more than 50% of the 125I-AcLDL degradation by macrophages [23].

Associations of Hmgcr with chemical compounds

• The failure of HMG-CoAR expression to increase during the feeding period in the PPAR alpha-null mice was associated with a decrease in hepatic nonesterified cholesterol content and an increase in cholesteryl ester compared with normal mice [24].
• Genes for HMG-CoA reductase and serotonin 1a receptor are on mouse chromosome 13 [17].
• Because this mevalonate pathway also produces several non-sterol isoprenoid compounds, the level of HMG-CoA reductase activity may coordinate many cellular processes and functions [18].
• Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein [25].
• These two defects may account for the overaccumulation of HMG-CoA reductase in CR200 cells and thereby for the resistance to compactin [20].

Physical interactions of Hmgcr

• 6-Nitrocholesterol has been shown to cause a 50% reduction in the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in animal cells in culture at 1.9 microM and it has relative binding affinity for the cytosolic oxysterol binding protein of 357 nM in cell-free extracts from the same cell line [26].

Enzymatic interactions of Hmgcr

• Mevalonate is the direct product of the rate-limiting step in cholesterol synthesis which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase [27].

Regulatory relationships of Hmgcr

• Furthermore, IL-10 suppressed HMG-CoA reductase expression in the HepG2 cells [28].
• Hence, these findings strongly suggest that statins' inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury [29].
• These data suggest that HMG-CoA reductase inhibitors can both inhibit cell proliferation and induce apoptosis in PASMCs through p27Kip1-independent pathways and may be important therapeutic agents in pulmonary arterial hypertension [30].
• Support for the role of a cytosolic oxysterol-binding protein in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was obtained by correlating the relative binding affinities of a wide range of oxysterols to their potency in suppressing HMG-CoA reductase activity in mouse fibroblast cell cultures [31].
• The accelerated degradation of HMG-CoA reductase induced by 25-hydroxycholesterol treatment was not affected by either NH4Cl or by inactivation of the ubiquitin degradative pathway [32].
• Functional ablation of insulin-induced sterol regulatory element-binding protein (SREBP)-2 by siRNA abolished HMGR expression and insulin-triggered VEGF protein release from keratinocytes [33].

Other interactions of Hmgcr

• However, a near-complete suppression of nuclear SREBP2 related to low Hmgcr mRNA levels was noticed only for gallstone-resistant AKR mice [34].
• The use of HMG-CoA reductase inhibitors (commonly called statins) in vitro and in vivo has proven them to be Abeta-lowering agents, however, the mechanism of action of these drugs is not yet known [35].
• Phytosterols significantly increased the activity of hepatic HMG-CoA reductase, and probucol significantly increased cholesterol 7 alpha-hydroxylase activity [36].
• Growth hormone increases low-density lipoprotein receptor and HMG-CoA reductase mRNA expression in mesangial cells [37].
• Treatment of cells with HMG-CoA reductase inhibitors enhanced N-CEase activity, whereas ACAT inhibitor decreased the activity [38].

Analytical, diagnostic and therapeutic context of Hmgcr

• We used gene targeting to knock out the mouse HMG-CoA reductase gene [18].
• In addition, we show by analytical subcellular fractionation and immunoelectron microscopy that HMG-CoA reductase protein and activity are localized both in the ER and peroxisomes in the CNS [22].
• To determine the mechanism for this increase in enzyme activity, in the present study we have shown by Western blot analysis that there is a 1.5-fold increase in the mass of HMG-CoA reductase after acute disruption of the barrier with acetone [39].
• Northern blot analysis demonstrated that after acute barrier disruption with acetone or tape-stripping, epidermal HMG-CoA reductase mRNA levels are increased [39].
• The hepatic HMG-CoA reductase activity was significantly lower in the naringin and lovastatin supplemented groups than in the control group, whereas the ACAT activity was unaffected [40].

References