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)

The extent to which lipid and apolipoprotein (apo) concentrations in tissue fluids are determined by those in plasma in normal humans is not known, as all studies to date have been performed on small numbers of subjects, often with dyslipidemia or lymphedema. Therefore, we quantified lipids, apolipoproteins, high density lipoprotein (HDL) lipids, and non-HDL lipids in prenodal leg lymph from 37 fasted ambulant healthy men. Lymph contained almost no triglycerides, but had higher concentrations of free glycerol than plasma. Unesterified cholesterol (UC), cholesteryl ester (CE), phosphatidylcholine (PC), and sphingomyelin (SPM) concentrations in whole lymph were not significantly correlated with those in plasma. HDL lipids, but not non-HDL lipids, were directly related to those in plasma. Lymph HDLs were enriched in UC. However, as the HDL cholesterol/non-HDL cholesterol ratio in lymph exceeded that in plasma, whole lymph nevertheless had a lower UC/CE ratio than plasma. Lymph also had a significantly higher SPM/PC ratio. The lymph/plasma (L/P) ratios of apolipoproteins were as follows: A-IV > A-I and A-II > C-III and E > B. Comparison with the L/P ratios of seven nonlipoprotein proteins suggested that apoA-IV was predominantly lipid free. Concentrations of apolipoproteins A-II, A-IV, C-III, and E in lymph, but not of apolipoproteins A-I or B, were positively correlated with those in plasma. The L/P ratios of apolipoproteins B, C-III, and E in two subjects with lipoprotein lipase (LPL) deficiency, and of apolipoproteins A-I and A-IV in a subject with lecithin:cholesterol acyltransferase (LCAT) deficiency, were low relative to those in normal subjects. Thus, the concentrations of lipids, apolipoproteins, and lipoproteins in human tissue fluid are determined only in part by their concentrations in plasma. Other factors, including the actions of LPL and LCAT, are at least as important.
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PMID:Lipid and apolipoprotein concentrations in prenodal leg lymph of fasted humans. Associations with plasma concentrations in normal subjects, lipoprotein lipase deficiency, and LCAT deficiency. 1094 20

A mouse model of insulin resistance and its associated dyslipidemia was generated by crossing mice expressing human apolipoprotein B (apoB) with mice lacking only brown adipose tissue (BATless). On a high fat diet, male apoB/BATless mice became obese, hypercholesterolemic, hypertriglyceridemic, and hyperinsulinemic compared with control apoB mice. Fast performance liquid chromatography revealed increased triglyceride concentrations in intermediate density lipoprotein/low density lipoprotein (LDL) and reduced high density lipoprotein cholesterol concentrations. Inhibition of lipolysis by the drug, tetrahydrolipostatin, demonstrated that very low density lipoprotein-sized particles were initially secreted. Metabolic studies employing Triton WR-1339 and either [(3)H]glycerol or [(3)H]palmitate showed that the hypertriglyceridemia in apoB/BATless mice was due to the increased synthesis and secretion of triglyceride. Furthermore, lipoprotein lipase and hepatic lipase activities were not defective. ApoB was also secreted at increased rates in the apoB/BATless mice. Similar levels of apoB mRNA in apoB and apoB/BATless mice indicated that apoB secretion was regulated post-transcriptionally. LDL receptor mRNA was increased in the apoB/BATless mice, indicating that the observed increase in apoB-lipoprotein secretion was not due to their decreased reuptake. Finally, mRNA levels of the large subunit of microsomal triglyceride transfer protein, a required component for very low density protein assembly, were not different between apoB and apoB/BATless mice. This rodent model should prove useful in exploring mechanisms underlying the regulation of apoB secretion in the context of insulin resistance.
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PMID:Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance. 1159 38

Increased circulating levels of nonesterified free fatty acids (NEFA) have been observed in such hyperinsulinemic states as obesity, impaired glucose tolerance, diabetes, and dyslipidemia where they have been causally linked to the development of insulin resistance and hyperinsulinemia. The concentration of NEFA in plasma is believed to have direct modifying effects on insulin secretion and clearance. It remains controversial whether acute increases in NEFA potentiate insulin secretion in human subjects. We studied the effect of an acute elevation of NEFA during lipid-heparin infusion compared to a glycerol-only control on glucose-stimulated insulin secretion and clearance during a 120-min hyperglycemic (10 mM) clamp in 7 healthy normoglucose-tolerant volunteers. The metabolic clearance rate of C-peptide (MCR(CP)) was measured in each subject during the study by simultaneous infusion of C-peptide. Insulin secretion rate (ISR) was calculated from deconvolution of C-peptide data after correction for the rate of C-peptide infusion. Clearance rate of insulin (MCR(INS)) was calculated based upon endogenous ISR. Plasma glucose (mg/dL): basal (90-115 min) 90.2 +/- 2.8 vs. 90.2 +/- 2.3; clamp (150-240 min) 180.5 +/- 2.8 vs. 180.9 +/- 1.3. Plasma insulin (pmol/L): prebasal (fasting) 29.6 +/- 10.0 vs. 29.8 +/- 10.6; basal (90-115 min) 30.1 +/- 9.2 vs. 34.5 +/- 12.1; second phase clamp (210-240 min) 127.6 +/- 18.2 vs. 182.5 +/- 17.3*. Plasma NEFA (mM): prebasal 0.47 +/- 0.08 vs. 0.52 +/- 0.09; basal 0.35 +/- 0.05 vs. 0.98 +/- 0.02*; clamp (122-240 min) 0.06 +/- 0.02 vs. 0.77 +/- 0.06*. ISR (pmol/min): prebasal 72.7 +/- 7.5 vs. 72.0 +/- 7.9; second phase clamp (210-240 min) 268.5 +/- 27.2 vs. 200.2 +/- 23.7. MCR(INS) (mL/min): prebasal 3393 +/- 488 vs. 3370 +/- 511; clamp 2284 +/- 505 vs. 1214 +/- 153* (*p < 0.05 glycerol vs. intralipid/heparin). This study demonstrates that acute NEFA elevation causes hyperinsulinemia due to a significant decrease in systemic insulin clearance without increasing rates of insulin secretion.
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PMID:Acute elevation of NEFA causes hyperinsulinemia without effect on insulin secretion rate in healthy human subjects. 1207 85

Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.
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PMID:Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. 1220 Jul 58

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

Glucose uptake into adipose and liver cells is known to up-regulate mRNA levels for various lipogenic enzymes such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). To determine whether the hexosamine biosynthesis pathway (HBP) mediates glucose regulation of mRNA expression, we treated primary cultured adipocytes for 18 h with insulin (25 ng/ml) and either glucose (20 mm) or glucosamine (2 mm). A ribonuclease protection assay was used to quantitate mRNA levels for FAS, ACC, and glycerol-3-P dehydrogenase (GPDH). Treatment with insulin and various concentrations of d-glucose increased mRNA levels for FAS (280%), ACC (93%), and GPDH (633%) in a dose-dependent manner (ED50 8-16 mm). Mannose similarly elevated mRNA levels, but galactose and fructose were only partially effective. l-glucose had no effect. Omission of glutamine from the culture medium markedly diminished the stimulatory effect of glucose on mRNA expression. Since glutamine is a crucial amide donor in hexosamine biosynthesis, we interpret these data to mean that glucose flux through the HBP is linked to regulation of lipogenesis through control of gene expression. Further evidence for hexosamine regulation was obtained using glucosamine, which is readily transported into adipocytes where it directly enters the HBP. Glucosamine was 15-30 times more potent than glucose in elevating FAS, ACC, and GPDH mRNA levels (ED50 approximately 0.5 mm). In summary: 1) GPDH, FAS, and ACC mRNA levels are upregulated by glucose; 2) glucose-induced up-regulation requires glutamine; and 3) mRNA levels for lipogenic enzymes are up-regulated by glucosamine. Hyperglycemia is the hallmark of diabetes mellitus and leads to insulin resistance, impaired glucose metabolism, and dyslipidemia. We postulate that disease pathophysiology may have a common underlying factor, excessive glucose flux through the HBP.
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PMID:Role of hexosamine biosynthesis in glucose-mediated up-regulation of lipogenic enzyme mRNA levels: effects of glucose, glutamine, and glucosamine on glycerophosphate dehydrogenase, fatty acid synthase, and acetyl-CoA carboxylase mRNA levels. 1275 50

Aquaporin adipose (AQPap) is a putative glycerol channel in adipocytes. It has recently been shown to be upregulated in insulin resistance stimulated by thiazolidinediones and inhibited by insulin. To further clarify regulation of AQPap gene expression, 3T3-L1 adipocytes were chronically treated with various hormones known to influence insulin sensitivity and adipocyte metabolism, and AQPap mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. Interestingly, treatment of 3T3-Ll adipocytes with 10 micro M isoproterenol, 10 ng/ml TNFalpha, and 100 nM dexamethasone for 16 h inhibited AQPap gene expression by 62 %, 60 %, and 39 %, respectively; angiotensin 2, growth hormone, and triiodothyronine did not have any effect. The inhibitory effects were dose-dependent with significant suppression detectable at concentrations as low as 1 nM isoproterenol, 1 ng/ml TNFalpha, and 10 nM dexamethasone. Furthermore, inhibition of AQPap gene expression could be almost completely reversed by pretreating 3T3-L1 adipocytes with the beta-adrenoceptor antagonist propranolol. Moreover, stimulation of Gs-proteins with cholera toxin and adenylyl cyclase with forskolin and dibutyryl-cAMP dramatically downregulated AQPap mRNA. Taken together, our results suggest that AQPap is an adipocyte-expressed glycerol channel selectively regulated and profoundly downregulated by hormones implicated in the pathogenesis of insulin resistance and dyslipidemia.
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PMID:Suppression of aquaporin adipose gene expression by isoproterenol, TNFalpha, and dexamethasone. 1277 65

Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder characterized by premature coronary artery disease, dyslipidemia, insulin resistance, and impaired adipose tissue free fatty acid (FFA) metabolism. Increased adipose tissue FFA flux towards the liver may, in part, contribute to reduced insulin sensitivity and hyperlipidemia in FCHL. It was the objective of the present study to evaluate the contribution of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene to FCHL traits related to adipocyte lipid metabolism, dyslipidemia, and insulin resistance. In a case-control panel consisting of 79 FCHL probands and 124 spouse controls, polymorphic marker D3S1259 and three intragenic PPARgamma variants, i.e., 161C > T, Pro12Ala, and Pro115Gln, were studied. The Pro115Gln variant was not found in any of the subjects. Allele frequencies of the 161C > T, Pro12Ala variants, and D3S1259 did not differ significantly between FCHL probands and spouses. In FCHL probands, individuals heterozygous or homozygous for the 161T allele had lower plasma concentrations of FFA (P < 0.05) and glycerol (P < 0.01). No significant associations were found in spouses. These findings identify PPARgamma as a quantitative trait locus for FFA and glycerol, against a background of insulin resistance for adipose tissue lipid metabolism, and therefore as a modifier gene in FCHL.
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PMID:Variants in the PPARgamma gene affect fatty acid and glycerol metabolism in familial combined hyperlipidemia. 1468 Sep 75

We recently observed that ANG II receptor blocker therapy improved the overproduction of triglyceride (TG) in fructose-fed rats and Zucker fatty rats with insulin resistance, which in turn suggests that ANG II may stimulate TG production. Accordingly, we investigated the effects of ANG II on TG production and the association with insulin resistance in normal rats. Male Wistar rats were continuously infused with ANG II (100 ng.min(-1).kg body wt(-1)) via an osmotic minipump for 14 days. ANG II infusion markedly elevated both the systolic and diastolic blood pressure. The plasma TG level increased twofold, but cholesterol was unchanged. ANG II infusion stimulated the TG secretion rate (TGSR) by twofold and increased the hepatic TG content by 31%. Lipogenesis determined by [2-(3)H]glycerol incorporation into hepatic TG was also significantly increased in ANG II-infused rats. The stimulatory effect of ANG II on TGSR was dose dependent and was not observed until 2 wk after the start of infusion. ANG II infusion significantly reduced insulin sensitivity index (SI) without affecting glucose effectiveness determined by Bergman's minimal model. The plasma TG level was positively correlated with TGSR (r = 0.88, P < 0.001) and inversely with SI (r = -0.80, P < 0.005). These results suggest that chronic ANG II infusion stimulates hepatic TG production, which is partly associated with simultaneous development of insulin resistance. Our results may suggest a new mechanism for the intimate association between hypertension and dyslipidemia.
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PMID:Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats. 1521 64

Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.
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PMID:Fructose, insulin resistance, and metabolic dyslipidemia. 1572 2


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