Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.
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PMID:HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. 1686 Dec 19

Lovastatin and extended-release (ER) niacin in a fixed dose combination (Advicor) is approved for the treatment of dyslipidemia. Since both drugs are extensively metabolized, this study investigated the bioavailability and pharmacokinetics of their co-administration following single-dose administration. In a 4-way crossover study 40 subjects received: two 1000/20 Advicor tablets (ADV), two 1000 mg niacin ER tablets (NSP), two 20mg lovastatin tablets (Mevacor; MEV), and two niacin ER 1000 mg tablets with two lovastatin 20mg tablets (NSP+MEV). Plasma was assayed for niacin, nicotinuric acid (NUA), lovastatin, lovastatin acid and HMGCoA reductase inhibition. Urine was assayed for niacin and its metabolites, NUA, N-methylnicotinamide and N-methyl-2pyridone-5-carboxamide. Least square mean ratios and 90% confidence intervals for C(max) and AUC((0-t)) were determined for NSP+MEV versus MEV or NSP, ADV versus MEV or NSP, and ADV versus NSP+MEV. Co-administration of niacin and lovastatin did not significantly influence C(max) and AUC((0-t)) of lovastatin, niacin, NUA and total urinary recovery of niacin and metabolites. A 22 to 25% decrease in lovastatin acid C(max) was observed while lovastatin acid AUC((0-t)) was not affected. The HMGCoA reductase inhibition C(max) and AUC((0-t)) were not affected indicating that the difference in lovastatin acid C(max) was not clinically relevant.
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PMID:The comparative bioavailability of an extended-release niacin and lovastatin fixed dose combination tablet versus extended-release niacin tablet, lovastatin tablet and a combination of extended-release niacin tablet and lovastatin tablet. 1757 Dec 83

The statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have emerged as the drugs of choice for patients with dyslipidemia and have been shown to reduce major cardiovascular adverse events in large-scale clinical trials for both primary and secondary prevention. Statins are generally safe; however, the results of clinical trials do demonstrate possibilities of significant adverse effects in liver and muscle. Moreover, the numbers from the trials may not reflect the real situation in daily practice because individuals at increased risk for hepatotoxicity are usually deliberately and carefully excluded in clinical trials. We presented an 85-year-old woman who had a marked elevation of ALT (up to 409 U/L) after treatment with fluvastatin 80 mg/day for 6 weeks. Hepatitis C was identified after this episode. The elevation of ALT resolved 10 weeks after discontinuation of fluvastatin. Re-institution of fluvastatin from 40 to 80 mg/day for 2 months only cause mild elevation of ALT. This case suggests that elevation of transaminases during statin therapy may not be solely ascribed to statins. Re-challenge with the same statin at lower doses or with other statins may help to identify the patients who can still be treated with drugs of this category.
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PMID:Marked elevation of liver transaminases after high-dose fluvastatin unmasks chronic hepatitis C: safety and re-challenge. 1796 56

Oxidized low-density lipoprotein (Ox-LDL) might be involved in the progression of renal disease. Ox-LDL stimulation of plasminogen activator inhibitor-1 (PAI-1) expression via transforming growth factor-beta (TGF-beta)/Smad signaling in mesangial cells required activation of extracellular signal-regulated kinase (ERK). Mevalonate depletion by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, decreases the levels of farnesyl pyrophosphate (FPP) for isoprenylation of Ras. We postulate that statins may ameliorate the Ox-LDL-induced mesangial matrix accumulation by inhibiting Ras/ERK activation with subsequent downregulation of TGF-beta target genes. Quiescent mesangial cells were incubated for 18 h with and without the presence of lovastatin before 50 microg/mL of Ox-LDL treatment for 1 h. Lovastatin inhibited markedly the stimulatory effects of Ox-LDL on ERK1/2 activation, nuclear Smad3 expression, TGF-beta1 and PAI-1 mRNA and protein expression, and PAI-1 luciferase activity. These inhibitory effects of lovastatin were reversed almost completely by mevalonate or FPP. Similar to lovastatin, FTI-277, which is an inhibitor of Ras farnesylation, decreased the Ox-LDL-induced activation of ERK/Smad3 and induction of TGF-beta1/PAI-1. These results indicate that lovastatin prevents the Ox-LDL-induced Ras/ERK activation that results in inhibition of Smad3 activation in mesangial cells with subsequent downregulation of TGF-beta target genes. Thus, statins seem to have antifibrotic effects through their anti-TGF-beta response that are relevant in the treatment of chronic renal disease with dyslipidemia.
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PMID:Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-beta1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells. 1806 Nov 25

Type 2 diabetes mellitus is associated with elevated plasma triglyceride levels, low high-density lipoprotein cholesterol, and a high incidence of cardiovascular disease. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates are frequently used in the treatment of diabetic dyslipidemia, but their specific impact on the inflammation processes involved in atherosclerosis remains to be fully characterized. The objective of this 2-group parallel study was to investigate the differential effects of a 6-week treatment with either atorvastatin 20 mg/d alone (n = 19) or micronized fenofibrate 200 mg/d alone (n = 19) on inflammation, cell adhesion, and oxidation markers in type 2 diabetes mellitus subjects with marked hypertriglyceridemia. In addition to the expected changes in lipid levels, atorvastatin decreased plasma levels of C-reactive protein (-26.9%, P = .004), soluble intercellular adhesion molecule 1 (-5.4%, P = .03), soluble vascular cell adhesion molecule 1 (-4.4%, P = .008), sE-selectin (-5.7%, P = .02), matrix metalloproteinase 9 (-39.6%, P = .04), secretory phospholipase A(2) (sPLA(2)) (-14.8%, P = .04), and oxidized low-density lipoprotein (-38.4%, P < .0001). On the other hand, fenofibrate had no significant effect on C-reactive protein levels and was associated with reduced plasma levels of sE-selectin only (-6.0%, P = .04) and increased plasma levels of sPLA(2) (+22.5%, P = .004). These results suggest that atorvastatin was potent to reduce inflammation, oxidation, and monocyte adhesion in type 2 diabetes mellitus subjects with marked hypertriglyceridemia, whereas fenofibrate decreased sE-selectin levels only and was associated with an elevation of sPLA(2) levels.
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PMID:Differential effect of atorvastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus. 1824 11

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) decrease serum cholesterol. Dyslipidemia is believed to be associated with the development of renal dysfunction. It was postulated that statins may reduce the development of renal dysfunction. The effect of statin use on the development of renal dysfunction in 197,551 patients (Department of Veterans Affairs, Veterans Integrated Service Network 16 [VISN16] database) was examined. Of these patients, 29.5% (58,332 patients) were statin users and 70.5% (139,219 patients) were not. Development of renal dysfunction was defined as doubling of baseline creatinine or increase in serum creatinine > or =0.5 mg/dl from the first to last measurement with a minimum of 90 days in between. During 3.1 years of follow-up, 3.4% of patients developed renal dysfunction. After adjustment for demographics, diabetes mellitus, smoking, hypertension, and other medications (mainly angiotensin-converting enzyme inhibitors, calcium channel blockers, and aspirin), use of statins decreased the odds of developing renal dysfunction by 13% (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82 to 0.92, p <0.0001). The beneficial effect of statins appeared to be independent of the decrease in cholesterol. Other variables that affected the development of renal dysfunction were age (OR 1.04, 95% CI 1.03 to 1.04, p <0.0001), diabetes (OR 1.77, 95% CI 1.68 to 1.86, p <0.0001), hypertension (OR 1.11, 95% CI 1.02 to 1.2, p = 0.0153), and smoking (OR 1.12, 95% CI 1.02 to 1.24, p = 0.0244). In conclusion, statin use may retard the development of renal dysfunction. The beneficial effect of statins in preventing the development of renal dysfunction appears to be independent of their lipid-lowering effect.
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PMID:Effect of statins on the development of renal dysfunction. 1835 17

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are extensively used to regulate dyslipidemia and to reduce atherosclerotic cardiovascular disease. In addition to effectively lowering cholesterol and low-density lipoprotein levels, rosuvastatin and certain other statins can also increase plasma high-density lipoprotein (HDL) cholesterol modestly. However, the mechanism of action of rosuvastatin on HDL metabolic processes is not understood. Using cultured human hepatoblastoma cells (Hep G2) as an in vitro model system, we assessed the effect of rosuvastatin on apolipoprotein (apo) A-I and apo A-II (the major proteins of HDL) synthesis and HDL catabolic processes. Rosuvastatin dose-dependently increased messenger RNA expression and de novo synthesis of apo A-I but not apo A-II. Rosuvastatin selectively increased the synthesis of HDL particles containing only apo A-I (LP A-I) but not particles containing both apo A-I and A-II (LP A-I + A-II). The HDL(3)-protein or HDL(3)-cholesterol ester uptake by Hep G2 cells was not affected by rosuvastatin. The apo A-I-containing particles secreted by rosuvastatin-treated Hep G2 significantly increased cholesterol efflux from fibroblasts. The data indicate that rosuvastatin increases hepatic apo A-I but not apo A-II messenger RNA transcription, thereby selectively increasing the synthesis of functionally active apo A-I-containing HDL particles, which mediate cholesterol efflux from peripheral tissues. We suggest that this mechanism of action of rosuvastatin to increase apo A-I production without apo A-I/HDL removal may result in increased apo A-I turnover that results in accelerated reverse cholesterol transport.
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PMID:Rosuvastatin selectively stimulates apolipoprotein A-I but not apolipoprotein A-II synthesis in Hep G2 cells. 1855 40

Elevated serum low-density lipoprotein cholesterol (LDL-C) and low serum high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic ischemic stroke. The National Cholesterol Education Panel and the American Heart Association have released guidelines for the treatment of dyslipidemia that stress LDL-C reduction using HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) and are applicable to individuals who have had or are at a high risk of having a stroke. Treatment of low HDL-C is a secondary goal of these guidelines and can be best achieved by using extended-release niacin (alone or in combination with statins) and fibrates. Early and aggressive treatment of dyslipidemia is an important component of a multimodality approach to stroke prevention.
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PMID:HDL-C and LDL-C: their role in stroke pathogenesis and implications for treatment. 1858 8

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.
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PMID:7-oxysterols modulate glucocorticoid activity in adipocytes through competition for 11beta-hydroxysteroid dehydrogenase type. 1902 97

South Asians have higher overall burden of coronary heart disease. South Asian migrants suffer from more severe and fatal coronary heart disease at younger age despite similar risk factors compared with local population. Elevated blood cholesterol contributes to atherosclerosis and heart disease and is one of the primary modifiable risk factor for these conditions. Since the discovery of a fungal metabolite that inhibits 3-hydroxy-3methyl-glutaryl-coenzyme A reductase, statins have emerged rapidly as the global leader in medical therapeutics designed to lower low-density lipoprotein cholesterol and had reduced mortality and morbidity from coronary heart disease when used for primary or secondary prevention. Despite the considerable burden imposed by cardiovascular disease, South Asians remain inadequately targeted for risk-reduction strategies, including screening and treatment for dyslipidemia.
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PMID:Statin therapy in South Asians-facts and future. 1926 68


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