Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Smoking is a leading cause of atherosclerosis acting trough a wide spectrum of mechanisms, notably the increase of the proatherogenic effect of dyslipidemia. However, a severe atherosclerotic disease is frequently observed in smokers who do not present an overt dyslipidemia. In the present study, we sought to determine if abnormalities in lipid metabolism occur in normolipidemic smokers, focusing especially on the components of intravascular remodeling of high-density lipoprotein (HDL) For this purpose, we measured lipid transfer proteins and enzymes involved in the reverse cholesterol transport (RCT) system in 29 adults: 15 smokers and 14 controls. The blood samples were drawn in the fasting state, immediately after the smokers smoked 1 cigarette. The composition of HDL particles was analyzed after isolation of HDL fractions by microultracentrifugation. We observed that normolipidemic smokers present higher total plasma and HDL phospholipids (PL) (P < .05), 30% lower postheparin hepatic lipase (HL) activity (P < .01), and 40% lower phospholipid transfer protein (PLTP) activity (P < .01), as compared with nonsmokers. The plasma cholesteryl ester transfer protein (CETP) mass was 17% higher in smokers as compared with controls (P < .05), but the endogenous CETP activity corrected for plasma triglycerides (TG) was in fact 57% lower in smokers than in controls (P < .01). Lipid transfer inhibitor protein activity was also similar in both groups. In conclusion, the habit of smoking induces a severe impairment of many steps of the RCT system even in the absence of overt dyslipidemia. Such an adverse effect might favor the atherogenicity of smoking.
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PMID:Smoking prevents the intravascular remodeling of high-density lipoprotein particles: implications for reverse cholesterol transport. 1525 77

Postheparin plasma hepatic lipase (HL) activity has been shown to correlate with features of the metabolic syndrome and type 2 diabetes in humans. We examined HL postheparin plasma enzyme activity, hepatocyte mRNA, and protein mass in the insulin-resistant, fructose-fed Syrian golden hamster, and the response of the insulin-sensitizing peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Male Syrian golden hamsters were treated for 5 weeks with 1) normal diet (DIET group), 2) 60% fructose diet (FRUC group), or 3) 60% fructose and rosiglitazone (20 mmol . kg(-1) . day(-1)) (FRUC+RSG group). Hepatocyte HL mRNA, protein mass, and postheparin plasma HL activity were increased in FRUC compared with DIET hamsters. FRUC+RSG hamsters had partial normalization of HL mRNA, mass, and activity. There was a shift in the size of LDL particles from large to small in FRUC animals and a shift back to large LDL size in FRUC+RSG. This is the first demonstration that HL hepatocyte mRNA, mass, and plasma enzymatic activity increase concomitantly with induction of an insulin-resistant state and can be partially normalized by treatment with an insulin sensitizer. The increase in HL in insulin-resistant states may play an important role in the typical dyslipidemia of these conditions, and reduction of HL could explain some of the beneficial effects of insulin sensitizers on the plasma lipid profile.
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PMID:Hepatic lipase mRNA, protein, and plasma enzyme activity is increased in the insulin-resistant, fructose-fed Syrian golden hamster and is partially normalized by the insulin sensitizer rosiglitazone. 1550 70

Impaired insulin action has been associated with diabetes, dyslipidemia and atherosclerotic vascular disease. The expression of insulin resistance results from the interaction of environmental and genetic factors. Human hepatic lipase (HL) is a lipolytic enzyme that plays a role in the metabolism of several lipoproteins, while insulin up-regulates the activity of HL via insulin-responsive elements in the HL promoter. We have examined the influence of -514 C/T polymorphism in the hepatic lipase gene promoter on insulin sensitivity in 59 healthy young subjects (30 males and 29 females). The volunteers were subjected to three dietary periods, each lasting four weeks. During the first period all subjects consumed a saturated fat (SFA)-enriched diet with 38% as fat (20% SFA, 12% monounsaturated fatty acids (MUFA) and 6% polyunsaturated fatty acids (PUFA)). In the second and third dietary periods, a randomized crossover design was used, consisting of a low fat, high carbohydrate diet (CHO diet) (< 10% SFA, 12% MUFA and 6% PUFA) and a high-MUFA, or Mediterranean diet, with < 10% SFA, 22% MUFA and 6% PUFA. We determined the in vivo insulin resistance using the insulin suppression test with somatostatin. Steady-state plasma glucose (SSPG) concentrations (a measure of insulin sensitivity) were significantly higher in men carriers of the -514T allele after the consumption of the SFA diet than after the CHO diet and the Mediterranean diet. This effect was not observed in women. Moreover, there were no significant differences in insulin sensitivity after the three diets in men and women with the CC genotype. In summary, our results show an improvement in insulin sensitivity in men with the -514T allele of the HL promoter polymorphism, when MUFA and carbohydrates are consumed instead of SFA fat.
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PMID:The -514 C/T polymorphism in the hepatic lipase gene promoter is associated with insulin sensitivity in a healthy young population. 1582 Nov

Lipoprotein lipase, HL, and endothelial lipase (EL) are proteoglycan-bound enzymes that regulate plasma lipoprotein levels through coordinated triglyceride (TG) lipase and phospholipase activity. We hypothesized that single nucleotide polymorphisms (SNPs) in lipase genes would have higher order impact on plasma lipoproteins beyond the influence of individual SNPs. In a sample of asymptomatic Caucasian subjects (n = 738), we used a two-stage approach, first identifying groups of subjects with similar multilocus lipase genotypes and then characterizing the relationships between genotype groups and plasma lipids. Using complementary methods, including a permutation test procedure and a mixed-effects modeling approach, we found a higher order interaction between four SNPs in three lipase genes (EL 2,237 3' untranslated region, EL Thr111Ile, HL -514C/T, and LPL HindIII) and plasma TG levels. Subjects who were heterozygous for all four lipase SNPs had significantly higher plasma TG levels beyond the effect of individual lipase SNPs and environmental factors, even after correcting for multiple comparisons. In conclusion, lipase genes had synergistic association with plasma TG beyond individual gene effects. Higher order multilocus genotype contributions to dyslipidemia and atherosclerotic cardiovascular disease need to be considered a priori because they may have an important effect even in the absence of significant main effects of the individual genes.
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PMID:Higher order lipase gene association with plasma triglycerides. 1596 89

Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.
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PMID:Effect of gene polymorphisms on lipoprotein levels in patients with dyslipidemia of metabolic syndrome. 1634 38

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.
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PMID:Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage. 1646 50

Cardiovascular disease (CVD) results from complex interactions between genetic and environmental factors. The evidence supports that gene-environment interactions modulate plasma lipid concentrations and potentially CVD risk. Several genes (eg, apolipoprotein A-I and A-IV, apolipoprotein E, and hepatic lipase) are providing proof-of-concept for the application of genetics in the context of personalized nutrition for CVD prevention. The spectrum of candidate genes has been expanding to incorporate those involved in intracellular lipid metabolism and especially those transcription factors (ie, peroxisome proliferator activator receptors) that act as sensors of nutrients in the cell (eg, polyunsaturated fatty acids) to trigger metabolic responses through activation of specific sets of genes. However, current knowledge is still very limited and so is the potential benefit of its application to clinical practice. Thinking needs to evolve from simple scenarios (eg, one single dietary component, a single nucleotide polymorphism and risk factor) to more realistic situations involving multiple interactions. One of the first situations where personalized nutrition is likely to be beneficial is in patients with dyslipidemia who require special intervention with dietary treatment. This process could be more efficient if the recommendations were carried out based on genetic and molecular knowledge. Moreover, adherence to dietary advice may increase when it is supported with information based on nutritional genomics, and a patient believes the advice is personalized. However, a number of important changes in the provision of health care are needed to achieve the potential benefits associated with this concept, including a teamwork approach with greater integration among physicians, food and nutrition professionals, and genetic counselors.
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PMID:Nutrigenetics, plasma lipids, and cardiovascular risk. 1681 24

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

Lipolysis is an important pathway in maintaining energy homeostasis through the degradation of triglycerides in adipose tissue and the release of fatty acids into the circulation as an energy source. However, an elevated level of circulating fatty acids leads to unfavorable metabolic effects such as insulin resistance and dyslipidemia. Cell surface receptors and intracellular components of the lipolytic pathway have been targeted to develop antilipolytic agents, among which are G-protein-coupled receptor agonists and lipase inhibitors. In addition, molecules that stimulate lipolysis have been tested in clinical trials as a treatment for obesity. Together, these molecules represent a diverse group of regulators for this pathway. This review will discuss strategies to target lipolysis and the major issues with representative small-molecule modulators of this pathway.
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PMID:Small-molecule compounds that modulate lipolysis in adipose tissue: targeting strategies and molecular classes. 1705 6

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


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