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)

At present, dyslipidemia is most commonly treated with lipid-altering pharmacological therapies. However, safety concerns regarding the use of these agents have prompted the need for safe and efficacious nonpharmacological lipid-altering interventions. One such natural therapy is the combination of plant sterols and endurance training. This combination lifestyle intervention has been shown to decrease total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations while increasing high-density lipoprotein (HDL) cholesterol concentrations. However, the mechanisms that underlie these positive lipid alterations have yet to be clarified. Thus, the purpose of this review is to evaluate individual effects of plant sterols and exercise training on lipid levels while attempting to elucidate the possible independent and synergistic mechanisms of action responsible for these modulations. Results reveal that plant sterols decrease both total and LDL cholesterol levels by reducing exogenous cholesterol absorption by way of cholesterol displacement in the intestinal lumen. Additionally, the intestinal membrane transport proteins, ABCG5, ABCG8, as well as NPC1L1, have also been implicated in plant sterol-mediated cholesterol lowering. Conversely, exercise decreases triglyceride levels by reducing hepatic very low-density lipoprotein secretion and increasing skeletal lipoprotein lipase activity. In addition, endurance training was shown to increase HDL cholesterol levels by way of HDL subfraction alterations, in conjunction with changing reverse cholesterol transport enzyme activities. Moreover, plant sterols and exercise may work synergistically to alter lipid levels by modulating lipoprotein transport, composition, release and metabolism. In sum, the present review lends further insight as to the metabolic benefits of adopting a healthy lifestyle, including plant sterols and endurance training, in the treatment of dyslipidemia.
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PMID:Plant sterols combined with exercise for the treatment of hypercholesterolemia: overview of independent and synergistic mechanisms of action. 1641 48

Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. 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. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.
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PMID:Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice. 1645 17

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.
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PMID:Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. 1647 80

Studies have shown an association between the lipoprotein lipase gene and dyslipidemia and atherosclerosis in some populations. The aim of this study was to investigate the association between the common lipoprotein lipase HindIII (T-G) and Ser447Ter (C-G) polymorphisms with dyslipidemia in Asian Indians, who are known to have very high rates of premature coronary artery disease. A total of 1,015 subjects, comprising 550 normal glucose-tolerant subjects and 465 patients with type 2 diabetes, were randomly selected from the Chennai Urban Rural Epidemiology Study. The total serum cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglyceride levels were assayed using enzymatic methods. Low-density lipoprotein cholesterol was calculated using the Friedewald formula. Genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism method. A significant association was found between the H+ allele of HindIII with low HDL cholesterol and elevated triglyceride levels. The Ser allele of Ser447Ter was also strongly associated with low HDL cholesterol levels. No association was found between the H+ allele and Ser Allele with the total or low-density lipoprotein cholesterol levels. Group-wise haplotype frequencies were generated using the expectation-maximization algorithm to detect differences in overall haplotype frequency profiles between the case-control groups. The haplotype analysis showed that the H+ Ser and H- Ter were the "high-risk" and "low-risk" haplotypes for low HDL cholesterol and elevated triglyceride levels, respectively. In conclusion, the H+ Ser haplotype of the lipoprotein lipase gene was associated with low HDL cholesterol levels and hypertriglyceridemia in Asian Indians.
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PMID:Association of lipoprotein lipase Hind III and Ser 447 Ter polymorphisms with dyslipidemia in Asian Indians. 1663 7

Human lipoprotein lipase (hLPL) deficiency, for which there currently exists no adequate treatment, leads to excessive plasma triglycerides (TGs), recurrent abdominal pain, and life-threatening pancreatitis. We have shown that a single intramuscular administration of adeno-associated virus (AAV) serotype 1 vector, encoding the human LPL(S447X) variant, results in complete, long-term normalization of dyslipidemia in LPL(/) mice. As a prelude to gene therapy for human LPL deficiency, we tested the efficacy of AAV1-LPL(S447X) in LPL(/) cats, which demonstrate hypertriglyceridemia (plasma TGs, >10,000 mg/dl) and clinical symptoms similar to LPL deficiency in humans, including pancreatitis. Male LPL(/) cats were injected intramuscularly with saline or AAV1-LPL(S447X) (1 x 10(11)-1.7 x 10(12) genome copies [GC]/kg), combined with oral doses of cyclophosphamide (0-200 mg/m(2) per week) to inhibit an immune response against hLPL. Within 3-7 days after administration of >or=5 x 10(11) GC of AAV1-LPL(S447X) per kilogram, the visible plasma lipemia was completely resolved and plasma TG levels were reduced by >99% to normal levels (10-20 mg/dl); intermediate efficacy (95% reduction) was achieved with 1 x 10(11) GC/kg. Injection in two sites, greatly limiting the amount of transduced muscle, was sufficient to completely correct the dyslipidemia. By varying the dose per site, linear LPL expression was demonstrated over a wide range of local doses (4 x 10(10)-1 x 10(12) GC/site). However, efficacy was transient, because of an anti-hLPL immune response blunting LPL expression. The level and duration of efficacy were significantly improved with cyclophosphamide immunosuppression. We conclude that AAV1-mediated delivery of LPL(S447X) in muscle is an effective means to correct the hypertriglyceridemia associated with feline LPL deficiency.
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PMID:Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. 1671 6

This systematic review attempted to summarize the associations between the Asn291Ser variant in the lipoprotein lipase (LPL) gene and dyslipidemia, the risk of type 2 diabetes mellitus (T2DM), and coronary heart disease (CHD). In addition, the relationships between the Asn291Ser variant and other metabolic diseases such as obesity and high blood pressure were also investigated in this systematic review. We systematically reviewed the literature by means of a meta-analysis. Twenty-one articles, including 19,246 white subjects, were selected for this meta-analysis. The summary standardized mean difference (SMD) of plasma triglyceride (TG) for carriers compared with noncarriers of the Asn291Ser variant was 3.23 (P < 0.00001). The summary SMD of plasma HDL-cholsterol (HDL-C) for carriers compared with noncarriers of the Asn291Ser variant was -3.42 (P < 0.0001). The summary SMD of the association of the Asn291Ser variant with plasma TG increased with increasing age and weight gain. Significant interactions between the LPL Asn291Ser variant and fasting glucose, T2DM, and CHD were seen (P = 0.02, 0.04, and 0.01, respectively). No significant interactions were seen between the LPL Asn291Ser variant and body mass index, waist-hip ratio, and blood pressure (P > 0.05). This meta-analysis indicates that the Asn291Ser variant in the LPL gene is a risk factor for dyslipidemia, characterized by hypertriglyceridemia and low HDL-C levels. And the Asn291Ser variant in the LPL gene predisposes to more severe dyslipidemia with increasing age and weight gain. Also, this meta-analysis shows that the LPL Asn291Ser variant is associated with CHD and T2DM.
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PMID:A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases. 1674 Dec 92

It remains unclear whether insulin improves dyslipidemia in patients with type 2 diabetes mellitus. Small dense low-density lipoprotein (sd-LDL) particles are recognized as a powerful risk factor for coronary heart disease and are often elevated in type 2 diabetes mellitus. We examined the effect of intensive insulin therapy on sd-LDL particles and triglyceride (TG)-rich lipoprotein subspecies. Intensive insulin therapy (insulin aspart [NovoRapid, Tokyo, Japan] before each meal and isophane insulin suspension at bedtime) was given to poorly controlled type 2 diabetic patients (n = 46) who were on high doses of sulfonylureas. Fasting serum samples were collected before and 14 days after the commencement of insulin therapy. Low-density lipoprotein size was measured by gradient gel electrophoresis, and the small dense LDL cholesterol (sd-LDL-C) concentration was measured by a new precipitation method. Chylomicrons (Svedberg flotation unit >400), very low-density lipoprotein 1 (VLDL1) (Sf, 60-400), and VLDL2 (Sf, 20-60) were separated by ultracentrifugation. Serum apolipoprotein B-48 and lipoprotein lipase levels were measured by the enzyme immunoassay method. Serum glucose and glycoalbumin levels were substantially decreased by insulin treatment. The LDL size increased (25.8-26.0 nm, P < .05) and the sd-LDL-C level was significantly reduced (44-34 mg/dL, P < .005). Apolipoproteins B-48 and C-III were decreased, whereas lipoprotein lipase was increased. Triglyceride levels in chylomicrons, VLDL1, and VLDL2 all showed a decrease. Changes of sd-LDL-C or LDL size were associated with changes of the TG levels in the major TG-rich lipoprotein subspecies. These results suggest that intensive insulin therapy decreases atherogenic sd-LDL particles by reducing TG in TG-rich lipoproteins. We did not find any specific relationship between VLDL1 and sd-LDL during insulin treatment.
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PMID:Intensive insulin therapy reduces small dense low-density lipoprotein particles in patients with type 2 diabetes mellitus: relationship to triglyceride-rich lipoprotein subspecies. 1678 58

Dyslipidemia, manifested by increased plasma triglyceride (TG), increased total and LDL-cholesterol concentrations and decreased HDL-cholesterol concentration, is an important risk factor for cardiovascular disease. Premenopausal women have a less atherogenic plasma lipid profile and a lower risk of cardiovascular disease than men, but this female advantage disappears after menopause. This suggests that female sex steroids affect lipoprotein metabolism. The impact of variations in the availability of ovarian hormones during the menstrual cycle on lipoprotein metabolism is not known. We therefore investigated whether very-low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B-100 (apoB-100) kinetics are different during the follicular (FP) and luteal phases (LP) of the menstrual cycle. We studied seven healthy, premenopausal women (age 27 +/- 2 yr, BMI 25 +/- 2 kg/m(2)) once during FP and once during LP. We measured VLDL-TG, VLDL-apoB-100, and plasma free fatty acid (FFA) kinetics by using stable isotope-labeled tracers, VLDL subclass profile by nuclear magnetic resonance spectroscopy, whole body fat oxidation by indirect calorimetry, and the plasma concentrations of lipoprotein lipase (LPL) and hepatic lipase (HL) by ELISA. VLDL-TG and VLDL-apoB-100 concentrations in plasma, VLDL-TG and VLDL-apoB-100 secretion rates and mean residence times, VLDL subclass distribution, FFA concentration and rate of appearance in plasma, whole body substrate oxidation, and LPL and HL concentrations in plasma were not different during the FP and the LP. We conclude that VLDL-TG and VLDL-apoB-100 metabolism is not affected by menstrual cycle phase.
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PMID:No effect of menstrual cycle phase on basal very-low-density lipoprotein triglyceride and apolipoprotein B-100 kinetics. 1683 98

Dyslipidemia and insulin resistance contribute to the endothelial cell dysfunction in hypertensive disorders of pregnancy (HDP) and increase the long-term risk of cardiovascular disease (CVD). The genes linking susceptibility to gestational hypertension (GH) and/or preeclampsia (PE) to the long-term risk of CVD are still unknown. We evaluated the potential association between 14 polymorphisms from six genes involved in lipid metabolism and insulin action and the risk of HDP: namely the lipoprotein lipase (LPL), hepatic lipase (LIPC), hormone sensitive lipase (LIPE), cholesteryl ester transfer protein (CETP), ApoCIII and ApoE gene polymorphisms. Overall, 169 women with HDP [proteinuria (PE) and gestational hypertension without proteinuria (GH)] and 169 controls matched for age and year of delivery were genotyped. Homozygosity of the -514T allele of the -514C > T polymorphism (LIPC gene) decreased the risk of GH (OR = 0.17, CI(95): 0.02-0.76), while there were more -60G carriers of the -60C > G LIPE gene polymorphism (OR = 3.51, CI(95):1.02-12.10) among GH cases, but not in PE cases. The common ApoCIII two-locus -482CC/3238CC genotype was lower in women with GH compared with controls (OR = 0.53, CI(95): 0.3-0.9). The combined frequency of at-risk genotypes was higher in cases of GH compared with controls [one at-risk genotype: OR = 3.38 (95% CI: 0.48-41.8); two or more at-risk genotypes: OR = 7.14 (95% CI: 1.21-92.3, P = 0.01)], suggesting a gene-dose effect. We conclude that the combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of GH, but seemingly not of PE.
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PMID:The combination of ApoCIII, hepatic lipase and hormono sensitive lipase gene polymorphisms suggests an association with susceptibility to gestational hypertension. 1731

Bacterial endotoxin/lipopolysaccharide (LPS)-induced cachexia is characterized by weight loss, anorexia, and a disturbance in lipid metabolism, namely, hypertriacylglycerolemia. The aim of this study in rats with acute endotoxicity induced by an injection of LPS was to investigate whether bezafibrate, a ligand for peroxisome proliferator-activated receptor alpha and a lipoprotein lipase (LPL) activator, improved cachectic conditions, including impaired lipid metabolism. Short-term administration of LPS in the rats resulted in impairment of triacylglycerol clearance in plasma after the intake of fresh cream. In addition, LPS increased whole-body energy expenditure, reduced fasting body weight and caused anorexia in the rats. Bezafibrate treatment resulted in significant improvements in LPS-induced dyslipidemia and anorexia, but had no effect on energy expenditure, respiratory quotient, or fasting body weight in the endotoxic rats. Administration of LPS was also associated with a decrease in the level of messenger RNA (mRNA) expression for LPL in white adipose tissue and skeletal muscle and an increase in the mRNA levels for uncoupling protein 3 in skeletal muscle. Bezafibrate treatment reversed the decline in LPL mRNA levels in white adipose tissue but not in the skeletal muscle tissue of the rats. The enhanced uncoupling protein 3 mRNA level in the endotoxic rats was not affected by bezafibrate treatment. Plasma concentration of leptin was increased by short-term LPS treatment. Bezafibrate decreased the level of plasma leptin significantly without affecting the level of leptin mRNA expression. These results suggest that bezafibrate may be an effective drug not only for impaired triacylglycerol metabolism, but also for anorexia in cachectic states induced by bacterial infections.
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PMID:Bezafibrate improves bacterial lipopolysaccharide-induced dyslipidemia and anorexia in rats. 1737 10


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