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

Current approaches to the treatment of lipid disorders are inadequate for a substantial number of patients with severe hyperlipoproteinemia, isolated low high-density lipoprotein (HDL) cholesterol levels, or other molecular disorders of lipoprotein metabolism. Therefore, dyslipidemias remain important targets for the development of novel therapies. Gene therapy is a logical therapeutic approach to monogenic lipoprotein disorders, such as homozygous familial hypercholesterolemia, familial lipoprotein lipase deficiency, familial lecithin-cholesterol acyltransferase deficiency, and abetalipoproteinemia, for which current therapies are inadequate. Gene therapy could also be used to increase expression of certain proteins, such as apolipoprotein A-I as a strategy to raise HDL cholesterol levels or apoE as a strategy for severe combined hyperlipidemia. With further progress in the development of vectors, gene therapy for severe dyslipidemia is likely to become a clinical reality.
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PMID:Gene therapy for dyslipidemia: clinical prospects. 1112 93

Patients with end-stage renal disease (ESRD) suffer from a secondary form of complex dyslipidemia consisting of both quantitative and qualitative abnormalities in serum lipoproteins resulting from alterations in lipoprotein metabolism and composition. The prominant features of uremic dyslipidemia are an increase in serum triglyceride levels (due to elevated very low density lipoprotein [VLDL]-remnants and intermediate-density lipoprotein [IDL]) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol often is normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass (sdLDL). The apolipoprotein B (apoB)-containing part of the lipoprotein may undergo modifications (enzymatic- and advanced glycation end-product [AGE]-peptide modification, oxidation, or glycosilation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. While LDL particles undergo a vicious cycle of accumulation and modification, reverse cholesterol transport is also impaired due to low lecithin:cholesterol acyltransferase (LCAT) and paraoxonase activity. Therefore, discoid HDL particles are structurally altered and hepatic cholesterol clearance is limited. The composition of HDL may also be altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is unclear at present. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Nevertheless, patients with renal disease belong to a very high cardiovascular risk group and dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in most patients. Because it is also still unclear whether we have available therapies with sufficient impact on LDL size, remnant lipoprotein-lowering, and restoration of HDL function, we urgently need the results from large scale intervention trials such as the 4D-trial and the CHORUS study.
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PMID:Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease. 1157 15

Hypoalphalipoproteinemia (HALP) is a dyslipidemia characterized by low HDL-cholesterol (HDL-C) levels with important genetic contribution. However, no common genetic mutations have been found to be associated with this disorder. We screened the promoter and coding sequence of apolipoprotein (apo) A-I and lecithin:cholesterol acyltransferase (LCAT) genes and the 5' apo C-III region by SSCP and heteroduplex analysis, and DNA sequencing in 66 unrelated subjects with recurrent low HDL-C levels. We also analyzed the N370S and L444P variants, in the glucocerebrosidase (GBA) gene by restriction fragment analysis. Three mutations in the apo A-I gene (L144R, W108R, g.1833C>T) and 3 mutations in the LCAT gene (S208T, I178T, IVS3-23C>A) were detected, in six heterozygous subjects. In addition, a novel polymorphic site in LCAT gene (g.4886C>T) has been identified. Allelic frequencies of polymorphisms g.(-636)C>A, g.(-625)G>A, g.(-620)T>del, g.(-479C>T and g.(-452)T>C, located upstream of the apo C-III gene, were in normal range, and no other mutation was found in this region. Two HALP subjects were found to carry the N370S mutation at GBA locus. In conclusion, 12% of HALP subjects were found to carry mutations in apo A-I, LCAT, or GBA genes, which could explain this phenotype. Our results confirm the molecular, genetic and phenotypic heterogeneity of HALP.
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PMID:Analysis of apolipoprotein A-I, lecithin:cholesterol acyltransferase and glucocerebrosidase genes in hypoalphalipoproteinemia. 1204 21

Abnormal lipid metabolism is a main cause of dyslipidemia, which is a major risk factor for coronary heart disease and obesity and is even linked to diabetic-dyslipidemic complications. Fifteen days of high-fat feeding in Charles Foster rats resulted in a significant increase in baseline serum lipid levels accompanied by pronounced dyslipidemia. Treatment with fish liver preparations (FLPs) from sea bass and the standard drug gemfibrozil produced a lowering of serum lipids and glucose levels, along with a fall in very-low-density and low-density lipoprotein and an increase in high-density lipoprotein levels. Simultaneously, reactivation of plasma postheparin lipolytic activity (PHLA) and lecithin:cholesterol acyltransferase (LCAT) activity was also observed. A positive correlation was observed between low-density lipoprotein activity and fecal bile acid excretion, which was enhanced on treatment with FLPs and gemfibrozil, indicating the catabolic process for normal lipids and cholesterol homeostasis. These data suggest that FLPs and gemfibrozil not only lower lipid intolerance but also reduce diabetic-dyslipidemic complications by activating peroxisome proliferator-activated receptors (PPAR).
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PMID:Beneficial effects of fish liver preparations of sea bass (Lates calcarifer) versus gemfibrozil in high fat diet-induced lipid-intolerant rats. 1293 23

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

Hypertriglyceridemia is a common pathological condition in humans of mostly unknown etiology. Here we report induction of dyslipidemia characterized by severe hypertriglyceridemia as a result of point mutations in human apolipoprotein A-I (apoA-I). Adenovirus-mediated gene transfer in apoA-I-deficient (apoA-I(-)(/)(-)) mice showed that mice expressing an apoA-I[E110A/E111A] mutant had comparable hepatic mRNA levels with WT controls but greatly increased plasma triglyceride and elevated plasma cholesterol levels. In addition, they had decreased apoE and apoCII levels and increased apoB48 levels in very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL). Fast protein liquid chromatography (FPLC) analysis of plasma showed that most of cholesterol and approximately 15% of the mutant apoA-I were distributed in the VLDL and IDL regions and all the triglycerides in the VLDL region. Hypertriglyceridemia was corrected by coinfection of mice with recombinant adenoviruses expressing the mutant apoA-I and human lipoprotein lipase. Physicochemical studies indicated that the apoA-I mutation decreased the alpha-helical content, the stability, and the unfolding cooperativity of both lipid-free and lipid-bound apoA-I. In vitro functional analyses showed that reconstituted HDL (rHDL) particles containing the mutant apoA-I had 53% of scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux capacity and 37% capacity to activate lecithin:cholesterol acyltransferase (LCAT) as compared to the WT control. The mutant lipid-free apoA-I had normal capacity to promote ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux. The findings indicate that subtle structural alterations in apoA-I may alter the stability and functions of apoA-I and high-density lipoprotein (HDL) and may cause hypertriglyceridemia.
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PMID:Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice. 1530 43

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.
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PMID:HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. 1550 47

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

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.
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PMID:Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. 1650 36


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