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)

Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.
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PMID:PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. 1256 15

Fenofibrate is the ligand for PPARalpha subtype that mediates the action of its agonists' in lipid metabolism. How fibrate exerts hypolipidemic effect? The mechanism is studied in a newly developed high-fat fructose enriched diet induced dyslipidemia-diabetic hamster model. Fenofibrate lowered the basal plasma lipids like TC, TG, PL, FFA, glycerol, VLDL, and LDL, but HDL was increased. The activity of lipoprotein lipase in liver, adipose tissue, and small intestine was upregulated. However, that of triglyceride lipase was downregulated in liver. It has also improved the insulin secretion and plasma glucose lowering, caused by impairment in insulin secretion due to high-fat load. The drug was found effective in reducing body weight and diet due to rise in leptin level. Fenofibrate also enhanced the fecal excretion of total lipids, cholic acid, and deoxycholic acid probably by the activation of 7alpha cholesterol hydroxylase enzyme. Thus, causing broad-spectrum lipid lowering along with inhibition of hepatic lipid biosynthesis and maintaining lipid-glucose homeostasis.
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PMID:Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. 1274 61

Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has been implicated in dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome, or AIDS. In vitro evidence indicates that some PIs reduce adipocyte lipoprotein (LPL) and hepatic lipase (HL) expression and activities. We examined whether LPL and HL activities are reduced in HIV-infected patients with dyslipidemia. Fasting serum lipids, glucoregulatory hormones, and postheparin LPL and HL activities, as well as whole body and regional adiposity, were measured in 19 HIV-seronegative controls, 9 HIV+ patients naive to all anti-HIV medications, 9 HIV+ patients naive to PIs, 9 HIV+ patients with prior PI experience but not currently receiving PIs, and 47 HIV+ patients receiving PI-HAART. The PI-HAART group had low LPL and HL activities. However, multiple linear regression analysis indicated that low postheparin LPL activity contributed only partially to HIV-dyslipidemia. Central adiposity and high C-peptide levels (an indicator of high insulin secretion) were stronger predictors of HIV-dyslipidemia. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia because the PI-naive group had low LPL and HL activities but had normal adiposity, C-peptide levels, and serum lipid and lipoprotein levels. HDL-cholesterol was lower in PI-HAART and PI-naive groups than seronegative controls and was directly associated with LPL activity. These findings suggest that HIV-dyslipidemia is mediated primarily by factors that influence triglyceride and lipoprotein synthesis (e.g., central adiposity and hyperinsulinemia) and mediated only partially by factors that influence triglyceride clearance (e.g., lipase activity).
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PMID:Visceral adiposity, C-peptide levels, and low lipase activities predict HIV-dyslipidemia. 1283 64

Excessive weight gain in a subset of intensively treated Diabetes Control and Complications Trial (DCCT) subjects was associated with higher waist to hip ratio; higher triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (ApoB) in the presence of small-dense LDL; and decreased high-density lipoprotein 2 cholesterol (HDL2-C), suggesting that weight gain in these subjects resulted in higher intraabdominal fat (IAF), and an atherosclerotic dyslipidemia mediated through hepatic lipase activity (HL). Objectives were to investigate relationships between IAF, HL, and dyslipidemia and to relate IAF to previous body mass index change during the DCCT. Sixty-one subjects were studied approximately 4 yr after DCCT closeout. IAF was positively related to HL (P < 0.001). IAF positively correlated with logTG (P < 0.001) and ApoB (P < 0.001), and negatively with LDL relative flotation rate (P < 0.001) and logHDL2-C (P = 0.001). HL accounted for most of the relationship between IAF with logHDL2-C and LDL relative flotation rate, and none of the relationship between IAF and logTG or ApoB. DCCT-related body mass index change accounted for a significant portion of logIAF variance measured 4 yr later (P < 0.001). Elevated IAF in subjects with type 1 diabetes was related to an atherosclerotic dyslipidemia similar to that seen in individuals without diabetes who have metabolic syndrome. DCCT-related weight gain positively correlated with subsequent IAF.
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PMID:Visceral obesity, hepatic lipase activity, and dyslipidemia in type 1 diabetes. 1284 91

Hypertriglyceridemia, low plasma concentrations of high density lipoproteins (HDL) and qualitative changes in low density lipoproteins (LDL) comprise the typical dyslipidemia of insulin resistant states and type 2 diabetes. Although isolated low plasma HDL-cholesterol (HDL-c) and apolipoprotein A-I (apo A-I, the major apolipoprotein component of HDL) can occur in the absence of hypertriglyceridemia or any other features of insulin resistance, the majority of cases in which HDL-c is low are closely linked with other clinical features of insulin resistance and hypertriglyceridemia. We and others have postulated that triglyceride enrichment of HDL particles secondary to enhanced CETP-mediated exchange of triglycerides and cholesteryl ester between HDL and triglyceride-rich lipoproteins, combined with the lipolytic action of hepatic lipase (HL), are driving forces in the reduction of plasma HDL-c and apoA-I plasma concentrations. The present review focuses on these metabolic alterations in insulin resistant states and their important contributions to the reduction of HDL-c and HDL-apoA-I plasma concentrations.
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PMID:Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. 1295 Nov 68

Dyslipidaemia, hallmarked by low HDL cholesterol and high plasma triglycerides, is a feature of insulin resistance and type 2 diabetes mellitus. These lipoprotein abnormalities represent major cardiovascular risk factors in these conditions. Among other factors, lipoprotein lipase (LPL), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) play an important role in an abnormal HDL metabolism in insulin resistance and type 2 diabetes mellitus. LPL hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. In insulin resistant states, a decreased post-heparin plasma LPL activity contributes to a low HDL cholesterol, whereas an increased activity of HL reduces HDL particle size by hydrolysing its triglycerides and phospholipids. High HL activity coincides with low HDL cholesterol. The esterification of free cholesterol by LCAT increases HDL particle size. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins. This cholesteryl ester transfer process results in lower HDL cholesterol and indirectly decreases HDL size. Plasma cholesterol esterification is unaltered or increased, whereas cholesteryl ester transfer is enhanced in type 2 diabetes mellitus, abnormalities which are probably related to the degree of hypertriglyceridaemia. It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain. Since the cholesteryl ester transfer process between lipoproteins provides a metabolic intermediate between low HDL cholesterol and high plasma triglycerides, hypertriglyceridaemia-associated accelerated transfer of cholesteryl ester out of HDL may be pathogenetically involved in the development of cardiovascular disease in insulin resistance and type 2 diabetes mellitus.
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PMID:Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus. 1465 31

Familial combined hyperlipidemia (FCHL) is characterized by elevated levels of serum total cholesterol (TC), triglyceride (TG), or both. The increased incidence of coronary artery diseases (CAD) in the patients with FCHL is believed to be caused by circulating atherogenic lipoproteins associated with the complex phenotype. Recent establishment of sensitive detection system for malondialdehyde-modified (MDA)-LDL, which is one of oxidized lipoproteins, showed its increased circulating level in the patients with CAD. In order to know the atherogenic lipoproteins resulted from the dyslipidemia observed in FCHL, we measured the serum MDA-LDL level in the patients. The circulating MDA-LDL level and the ratio of MDA-LDL and LDL-C in FCHL were significantly higher (P<0.05) than those in control, which are adjusted about the age, serum TC, LDL-C and HDL-C levels, respectively. Furthermore, the circulating MDA-LDL level and the ratio of MDA-LDL and LDL-C were negatively correlated (R=-0.635, P<0.01 and R=-0.702, P<0.01, respectively) with hepatic lipase (HL) activity in FCHL. The serum MDA-LDL level and the ratio of MDA-LDL and LDL-C were in the subjects with T/T genotypes in the HL C-514T polymorphism were significantly increased compared to those with C/C genotype, respectively. The subjects with T/T genotype showed the activities to 65 and 79% of those in the subjects with C/C genotype in male and female, respectively. The intima-media thickness (IMT) of carotid artery was significantly higher (P<0.05) in the subjects with T/T genotype than those with C/C genotype in male. These findings indicate that the circulating MDA-LDL level is possibly contributing the atherogenic process in FCHL, and the common HL polymorphism might be a determinant of the serum level of oxidized LDL in the patients with FCHL.
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PMID:Increased circulating malondialdehyde-modified LDL in the patients with familial combined hyperlipidemia and its relation with the hepatic lipase activity. 1470 74

In many industrialized nations, obesity is now considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as the metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia and hypertension, which are all recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public health problem. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining bodyweight loss. For example, phentermine may result in modest bodyweight loss through suppression of appetite, but potential cardiovascular adverse effects exist and the efficacy is mainly short-term. Sibutramine, an inhibitor of serotonin and norepinephrine (noradrenaline) reuptake, may increase satiety and result in modest bodyweight loss. However, cardiovascular adverse effects may occur in susceptible patients. Nonetheless, sibutramine is one of the few drugs that has been approved by the US Food and Drug Administration (FDA) for bodyweight loss. Orlistat, a lipase inhibitor, is also approved by the FDA for bodyweight loss but may have bothersome gastrointestinal adverse effects, especially among patients who do not adhere to the recommended low-fat diet. Ongoing studies continue to evaluate other drug treatments that may result in bodyweight reduction through a number of different mechanisms. It is anticipated that the development of effective and well tolerated antiobesity drugs will elevate the pharmacologic treatment of obesity to the status of other cardiovascular risk factors and metabolic disorders. This may be especially important given that dyslipidemia, hypertension and type 2 diabetes mellitus are often secondary to, or exacerbated by, obesity.
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PMID:Pharmacotherapy of obesity: currently marketed and upcoming agents. 1472 70

In population-based studies, dyslipidemia related to insulin resistance (high triglyceride level and low high-density lipoprotein cholesterol level) is a risk factor for type 2 diabetes. Therefore, variants in genes regulating lipid and lipoprotein metabolism are potential candidate genes for diabetes. We investigated whether the G-250A polymorphism of the hepatic lipase gene (LIPC) predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. This study randomized subjects to either the intervention group (lifestyle modification aimed at weight loss, such as changes in diet and increased physical exercise) or the control group. Genotyping at position -250 of the LIPC gene was performed with PCR amplification, DraI enzyme digestion, and gel electrophoresis in 490 subjects with IGT whose DNA was available. In the entire study population, the conversion rate to type 2 diabetes was 17.8% among subjects with the G-250G genotype and 10.7% among subjects with the -250A allele (P = 0.032). In univariate analysis, the odds ratio for the G-250G genotype to predict the conversion from IGT to type 2 diabetes was 1.80 (95% confidence interval, 1.05-3.10; P = 0.034). In multivariate logistic regression analysis, the G-250G genotype predicted the conversion to diabetes independently of the study group (control or intervention), gender, weight, waist circumference at baseline, and change in weight and waist circumference. In the intervention group, 13.0% of subjects with the G-250G genotype and 1.0% of the subjects with the -250A allele converted to diabetes (P = 0.001). We conclude that the G-250G genotype of the LIPC gene is a risk factor for type 2 diabetes. Therefore, genes regulating lipid and lipoprotein metabolism may be potential candidate genes for type 2 diabetes.
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PMID:The G-250A promoter polymorphism of the hepatic lipase gene predicts the conversion from impaired glucose tolerance to type 2 diabetes mellitus: the Finnish Diabetes Prevention Study. 1512 13

Hepatic lipase hydrolyses triglycerides and phospholipids in all major classes of lipoproteins. The -514C-->T genetic variation in the hepatic lipase gene promoter was found to be associated with diminished lipase activity, dyslipidemia, and atherosclerosis. We investigated whether this polymorphism associates with hyperinsulinemia and insulin resistance in 535 normal glucose-tolerant Germans. Only in homozygous individuals (22 subjects), the T allele (frequency: 18.1 %) was significantly associated with elevated glucose concentrations after 120 min of oral glucose tolerance test (p = 0.05) and with elevated fasting concentrations of insulin (p = 0.03), triglycerides (p < 0.01), total and HDL-cholesterol (p = 0.02), as determined by multivariate linear regression analysis. In a recessive model (C/C+C/T vs. T/T), T/T was associated with decreased insulin sensitivity index (p = 0.03) as calculated from oral glucose tolerance test data (n = 535), but not with the glucose infusion rate during hyperinsulinemic euglycemic clamp (n = 218). In conclusion, we have provided evidence that, among the metabolic parameters tested, the hepatic lipase -514C-->T gene polymorphism correlates with elevated fasting insulin concentrations in a German population. Since no corresponding difference in insulin sensitivity was seen in the clamp-subgroup, an effect of this polymorphism on insulin clearance has to be considered.
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PMID:Association of the -514C-->T polymorphism in the hepatic lipase gene (LIPC) promoter with elevated fasting insulin concentrations, but not insulin resistance, in non-diabetic Germans. 1515 10


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