MedWorm: Lipidology

Lp(a) predicts carotid stenosis and occlusion, but not carotid plaque area

MedWire News - Lipidology — Sat, 05 Jul 2008 10:28:05 +0100

Lipoprotein (Lp)(a) is a significant independent predictor for carotid stenosis and occlusion, but not carotid plaque area, report investigators. (Source: MedWire News - Lipidology)

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Removal of oxldl dramatically improves atherosclerotic prognosis in mice

MedWire News - Lipidology — Fri, 04 Jul 2008 10:10:09 +0100

Researchers report that removal of oxidized low-density lipoprotein from the circulation of mice almost completely halts atherosclerotic progression compared with controls. (Source: MedWire News - Lipidology)

Link between cvd risk and high lp(a) is weakened by hrt

MedWire News - Lipidology — Thu, 03 Jul 2008 10:35:33 +0100

Researchers report that the previously observed relationship between high lipoprotein (Lp)(a) and increased risk for cardiovascular disease is weakened in women taking hormone replacement therapy. (Source: MedWire News - Lipidology)

Low hdl cholesterol increases risk for memory problems in middle age

MedWire News - Lipidology — Wed, 02 Jul 2008 11:03:54 +0100

Low levels of high-density lipoprotein cholesterol are associated with memory deficit and decline in middle-aged individuals, report investigators in the journal Arteriosclerosis, Thrombosis, and Vascular Biology. (Source: MedWire News - Lipidology)

Cetp inhibitor anacetrapib shows initial promise

MedWire News - Lipidology — Tue, 01 Jul 2008 10:21:46 +0100

The novel cholesteryl ester transfer protein inhibitor anacetrapib successfully increases high-density lipoprotein cholesterol and reduces low-density lipoprotein cholesterol with no apparent adverse side effects, report investigators. (Source: MedWire News - Lipidology)

Adverse lipid profile linked to increased carotid imt in obese children

MedWire News - Lipidology — Mon, 30 Jun 2008 00:00:00 +0100

Researchers report that dyslipidemia but not the metabolic syndrome is associated with increased carotid intima-media thickness in obese children. (Source: MedWire News - Lipidology)

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Statin efficacy in aortic stenosis may be disease stage related

MedWire News - Lipidology — Mon, 30 Jun 2008 00:00:00 +0100

Statin treatment is effective at slowing progression of aortic valve sclerosis and mild but not moderate aortic stenosis, show results from a retrospective analysis. (Source: MedWire News - Lipidology)

Epa supplementation reduces cad events in dyslipidemic individuals

MedWire News - Lipidology — Sat, 28 Jun 2008 17:43:22 +0100

JELIS study researchers report that eicosapentaenoic acid significantly reduces the incidence of coronary artery disease events in patients with high triglycerides and low levels of high-density lipoprotein cholesterol. (Source: MedWire News - Lipidology)

Atorvastatin 'cost-effective' for reducing diabetic cardiovascular risk

MedWire News - Lipidology — Thu, 26 Jun 2008 23:03:20 +0100

Atorvastatin treatment is a cost-effective way of preventing cardiovascular disease in patients with Type 2 diabetes according to French financial guidelines, report researchers. (Source: MedWire News - Lipidology)

Lipoprotein binding preference of cd36 is altered by filipin treatment

Lipids in Health and Disease — Thu, 26 Jun 2008 04:00:00 +0100

The class B scavenger receptor CD36 binds multiple ligands, including oxidized and native lipoprotein species. CD36 and the related receptor SR-B1 have been localized to caveolae, domains that participate in cell signaling, transcytosis, and regulation of cellular cholesterol homeostasis. Previous work has indicated that the ligand preference of CD36 may depend on the cell type in which it is expressed. To determine if the presence or absence of caveolae is the determining factor for lipoprotein preference, we treated CHO-CD36 and C32 cells with filipin. Filipin treatment rapidly increased the binding capacity of CD36 for the native lipoproteins HDL and LDL, but did not affect the binding capacity of CD36 for oxidized LDL. Filipin treatment affected the distribution of caveolin and CD36 suggesting that the presence caveolae may modulate the ligand preference of CD36. However, its molecular mechanism how CD36 and caveolin interaction in regulating lipoprotein transport remains to be further studied. (Source: Lipids in Health and Disease)

Eicosapentaenoic acid helps reduce stroke recurrence in jelis trial

MedWire News - Lipidology — Wed, 25 Jun 2008 23:24:31 +0100

Patients who have suffered previous stroke experience reduced recurrence if they are given eicosapentanenoic acid in addition to a statin, report researchers from the JELIS trial. (Source: MedWire News - Lipidology)

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Cetp genotypes linked to higher hdl cholesterol and lower coronary risk

MedWire News - Lipidology — Wed, 25 Jun 2008 00:00:00 +0100

A comprehensive meta-analysis has shown that rare alleles of three common cholesteryl ester transfer protein gene variants are associated with elevated high-density lipoprotein cholesterol and a correspondingly reduced coronary risk. (Source: MedWire News - Lipidology)

Statin-related changes in oxldl biomarkers do not reflect atherosclerotic progression

MedWire News - Lipidology — Wed, 25 Jun 2008 00:00:00 +0100

Statin-related changes in oxidized low-density lipoprotein biomarker concentrations do not correlate with measures of coronary lumen dimensions or atheroma volume, show study results. (Source: MedWire News - Lipidology)

Acs patients with previous cabg benefit from intensive statin therapy

MedWire News - Lipidology — Tue, 24 Jun 2008 00:00:00 +0100

Researchers report that acute coronary syndrome patients who have previously undergone coronary artery bypass grafting gain similar benefit from intensive statin therapy as those who have not, despite a generally increased risk for adverse cardiac events. (Source: MedWire News - Lipidology)

Elevated estrogen levels linked to unfavorable lipid profile in men

MedWire News - Lipidology — Tue, 24 Jun 2008 00:00:00 +0100

Estradiol and estrone elevations in men cause an unfavorable lipid profile at an early age, report investigators in the journal Atherosclerosis. (Source: MedWire News - Lipidology)

Cac score better predictor of cvd events than carotid imt

MedWire News - Lipidology — Tue, 24 Jun 2008 00:00:00 +0100

Measurement of coronary artery calcium score is a better subclinical predictor of future cardiovascular disease events than carotid intima-media thickness, report scientists. (Source: MedWire News - Lipidology)

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Novel pcsk9 variant causal for autosomal dominant hypercholesterolemia

MedWire News - Lipidology — Mon, 23 Jun 2008 22:40:10 +0100

A newly discovered variant of the gene encoding proprotein convertase subtilisin/kexin type 9 in a Spanish population may directly contribute to autosomal dominant hypercholesterolemia, report researchers in the Journal of Clinical Endocrinology and Metabolism. (Source: MedWire News - Lipidology)

Icd patients have high omega-3 fatty acid levels in blood

MedWire News - Lipidology — Mon, 23 Jun 2008 00:00:00 +0100

Individuals with implantable cardioverter defibrillators who have high levels of omega-3 fatty acids in their red blood cells have an increased risk for ventricular arrhythmias, report investigators. (Source: MedWire News - Lipidology)

Soy isoflavone genistein inhibits human adipocyte differentiation

MedWire News - Lipidology — Mon, 23 Jun 2008 00:00:00 +0100

The soy isoflavone genistein inhibits adipogenesis by suppression of adipocyte lipid accumulation, adipocyte-specific genes, and estrogen receptor α and β, show study results. (Source: MedWire News - Lipidology)

Fatty liver disease may be earliest pathogenic event of metabolic syndrome

MedWire News - Lipidology — Fri, 20 Jun 2008 21:37:00 +0100

Fatty liver disease is independently associated with insulin resistance and may be one of the earliest signs of the metabolic syndrome, report investigators in the journal Metabolism: Clinical and Experimental. (Source: MedWire News - Lipidology)

Obesity has negative effect on chd risk through residual insulin resistance

MedWire News - Lipidology — Fri, 20 Jun 2008 00:00:00 +0100

Researchers report that adiposity has a residual negative effect on insulin sensitivity, and therefore future cardiovascular risk, in obese individuals treated for coronary heart disease. (Source: MedWire News - Lipidology)

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Combined pravastatin and irbesartan reduces oxldl and spla2-iia activity

MedWire News - Lipidology — Fri, 20 Jun 2008 00:00:00 +0100

Combined treatment with pravastatin and the angiotensin II type 1 receptor blocker irbesartan reduces activity of the coronary event predictor secretory phospholipase A2 type IIA and oxidized low-density lipoprotein in patients with coronary artery disease, research shows. (Source: MedWire News - Lipidology)

Lipid-rich plaque may predict post-stent implantation myocardial injury

MedWire News - Lipidology — Thu, 19 Jun 2008 00:00:00 +0100

Lipid-rich, large-volume plaques are associated with increased risk for embolic events following coronary artery stent implantation, report researchers. (Source: MedWire News - Lipidology)

Increasing trend for obesity observed in german children and adolescents

MedWire News - Lipidology — Thu, 19 Jun 2008 00:00:00 +0100

The percentage of German children with a body mass index above the 97th percentile significantly increased between 1999 and 2006, report investigators. (Source: MedWire News - Lipidology)

Infected adipocytes may contribute to chronic inflammation related cvd

MedWire News - Lipidology — Thu, 19 Jun 2008 00:00:00 +0100

Adipocyte cell infections lead to increased expression of interleukin-6, potentially contributing to the chronic inflammatory state associated with development of cardiovascular disease and Type 2 diabetes, show study results. (Source: MedWire News - Lipidology)

Mutant hmgcr mrna associated with reduced statin response

MedWire News - Lipidology — Wed, 18 Jun 2008 22:28:40 +0100

Study findings suggest that increased expression of a shortened transcript of the HMGCR gene produces smaller than usual reductions in plasma lipids in response to simvastatin treatment. (Source: MedWire News - Lipidology)

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Transcription factor xbp1 needed for normal fatty acid synthesis in the liver

MedWire News - Lipidology — Wed, 18 Jun 2008 00:00:00 +0100

Researchers report in the journal Science that the transcription factor X-box binding protein 1 plays a role in regulating lipid synthesis in the liver. (Source: MedWire News - Lipidology)

Mitral valve calcification more common with tricuspid than biscuspid aortic valves

MedWire News - Lipidology — Wed, 18 Jun 2008 00:00:00 +0100

Mitral annular calcification occurs more frequently in individuals with aortic stenosis who have tricuspid as opposed to bicuspid aortic valves, report investigators from the ASTRONOMER study. (Source: MedWire News - Lipidology)

Crp poor predictor cv outcomes after acute coronary syndrome

MedWire News - Lipidology — Tue, 17 Jun 2008 04:27:11 +0100

The inflammatory marker C-reactive protein does not significantly predict adverse cardiovascular outcomes after hospitalization for acute coronary syndrome, report investigators. (Source: MedWire News - Lipidology)

Human mtdna variants linked to ldl cholesterol level in athletes

MedWire News - Lipidology — Mon, 16 Jun 2008 00:00:00 +0100

Low-density lipoprotein cholesterol level is associated with mitochondrial DNA haplogroup in athletes, report investigators in the journal Mitochondrion. (Source: MedWire News - Lipidology)

Community initiative brings significant ldl cholesterol reductions

MedWire News - Lipidology — Mon, 16 Jun 2008 00:00:00 +0100

A closely monitored lipid-lowering initiative by community based physicians resulted in significant improvements in participants' low-density lipoprotein cholesterol levels, show study results. (Source: MedWire News - Lipidology)

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Apo b and a-i levels predict ischemic stroke risk in patients with chd

MedWire News - Lipidology — Fri, 13 Jun 2008 22:59:47 +0100

Levels of pro-atherogenic apolipoprotein B and anti-atherogenic apo A-I independently predict ischemic stroke in patients with coronary heart disease, report investigators in the Journal of the Neurological Sciences. (Source: MedWire News - Lipidology)

[commentary] errata. pcsk9 function and physiology

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

PCSK9 has exploded onto center stage of plasma cholesterol metabolism, raising hopes for a new strategy to treat hypercholesterolemia. PCSK9 in a plasma protein that triggers increased degradation of the LDL receptor. Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease. Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease. Two papers in this issue of the Journal of Lipid Research exemplify the rapid pace of progress in understanding PCSK9 molecular interactions and physiology. Dr. Shilpa Pandit and coworkers from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-of-function missense mutations in PCSK9. Dr. Jay Horton's group at UT Southwestern describe the kinetics and metabolism of PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland. (Source: The Journal of Lipid Research)

[calendar] calendar

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

(Source: The Journal of Lipid Research)

[errata] errata. pcsk9 function and physiology

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

[methods] pancreatic contamination of mesenteric adipose tissue samples can be avoided by adjusted dissection procedures

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Mesenteric adipose tissue, located in the mesenterium of the intestines, is believed to play a central role in the development of obesity-related diseases. We have found that mesenteric fat samples harvested from rodents are frequently of poor quality, exhibiting partly degraded RNA. To investigate the background for this observation, we screened adipose tissue samples from two independent studies on rodents for markers of different tissues and cell types. We found that mesenteric adipose tissue samples of low quality are "contaminated" by pancreatic tissue. To locate the affected area, we dissected the mesenteric fat depots from 14 mice and measured abundance of pancreas-specific gene expression and amylase activity. As expected, we observed that the proximal section of the mesenterium, located near the pancreas, expressed pancreatic markers, whereas the distal sections did not. Approximately one-third of the mesenteric adipose tissue depots contained pancreatic tissue. Because the boundary between pancreas and mesenteric fat cannot be easily distinguished during dissection, we conclude that investigators should routinely exclude the proximal section of the mesenteric adipose tissue depot to avoid pancreatic contamination. (Source: The Journal of Lipid Research)

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[research articles] evolution of the bile salt nuclear receptor fxr in vertebrates

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Bile salts, the major end metabolites of cholesterol, vary significantly in structure across vertebrate species, suggesting that nuclear receptors binding these molecules may show adaptive evolutionary changes. We compared across species the bile salt specificity of the major transcriptional regulator of bile salt synthesis, the farnesoid X receptor (FXR). We found that FXRs have changed specificity for primary bile salts across species by altering the shape and size of the ligand binding pocket. In particular, the ligand binding pockets of sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) FXRs, as predicted by homology models, are flat and ideal for binding planar, evolutionarily early bile alcohols. In contrast, human FXR has a curved binding pocket best suited for the bent steroid ring configuration typical of evolutionarily more recent bile acids. We also found that the putative FXR from the sea squirt Ciona intestinalis, a chordate invertebrate, was completely insensitive to activation by bile salts but was activated by sulfated pregnane steroids, suggesting that the endogenous ligands of this receptor may be steroidal in nature. Our observations present an integrated picture of the coevolution of bile salt structure and of the binding pocket of their target nuclear receptor FXR. (Source: The Journal of Lipid Research)

[research articles] scavenger receptor class b type i localizes to a late endosomal compartment

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Scavenger receptor class B type I (SR-BI) has an established role in mediating the selective uptake of cholesterol from HDL in hepatocytes, steroidogenic cells, and other tissues. SR-BI is present on the plasma membrane but also localizes to stable intracellular compartments of unknown function. Using indirect immunofluorescence and subcellular fractionation, we have investigated the subcellular distribution of SR-BI. We report that red fluorescent protein-tagged mouse SR-BI (RFP-mSR-BI) colocalizes with the late endosomal and lysosomal markers, Rab7, LBPA, and Rab9. In addition, endogenous SR-BI is also found on lysosomes and colocalizes with LAMP-2 in primary hepatocytes. Furthermore, we demonstrate that the trafficking of SR-BI through these compartments is Rab7 dependent. Interestingly, filipin staining indicates accumulation of lysosomal cholesterol in SR-BI-deficient (–/–) as compared with wild-type hepatocytes. In addition to its role as a plasma membrane receptor, SR-BI may function in cholesterol trafficking from late endosomes/lysosomes. (Source: The Journal of Lipid Research)

[research articles] dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Accumulation of visceral fat is a key phenomenon in the onset of obesity-associated metabolic disorders. Macrophage infiltration induces chronic mild inflammation widely considered as a causative factor for insulin resistance and eventually diabetes. We previously showed that >90% of macrophages infiltrating the adipose tissue of obese animals and humans are arranged around dead adipocytes, forming characteristic crown-like structures (CLS). In this study we quantified CLS in visceral and subcutaneous depots from two strains of genetically obese mice, db/db and ob/ob. In both strains, CLS were prevalent in visceral compared with subcutaneous fat. Adipocyte size and CLS density exhibited a positive correlation both in visceral and in subcutaneous depots; however, the finding that adipocyte size was smallest and CLS density highest in visceral fat suggests a different susceptibility of visceral and subcutaneous adipocytes to death. Visceral fat CLS density was 3.4-fold greater in db/db than in ob/ob animals, which at the age at which our experimental strain was used are more prone to glucose metabolic disorders. (Source: The Journal of Lipid Research)

[research articles] the hepatic uptake of vldl in lrp-ldlr-/-vldlr-/- mice is regulated by lpl activity and involves proteoglycans and sr-bi

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp–ldlr–/–vldlr–/– mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp–ldlr–/–vldlr–/– mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI. (Source: The Journal of Lipid Research)

[research articles] elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Hepatic fatty acid elongase-5 (Elovl-5) plays an important role in long chain monounsaturated and polyunsaturated fatty acid synthesis. Elovl-5 activity is regulated during development, by diet, hormones, and drugs, and in chronic disease. This report examines the impact of elevated Elovl-5 activity on hepatic function. Adenovirus-mediated induction of Elovl5 activity in livers of C57BL/6 mice increased hepatic and plasma levels of dihomo--linolenic acid (20:3,n-6) while suppressing hepatic arachidonic acid (20:4,n-6) and docosahexaenoic acid (22:6,n-3) content. The fasting-refeeding response of peroxisome proliferator-activated receptor -regulated genes was attenuated in mice with elevated Elovl5 activity. In contrast, the fasting-refeeding response of hepatic sterol-regulatory element binding protein-1 (SREBP-1)-regulated and carbohydrate-regulatory element binding protein/Max-like factor X-regulated genes, Akt and glycogen synthase kinase (Gsk)-3β phosphorylation, and the accumulation of hepatic glycogen content and nuclear SREBP-1 were not impaired by elevated Elovl5 activity. Hepatic triglyceride content and the phosphorylation of AMP-activated kinase and Jun kinase 1/2 were reduced by elevated Elovl5 activity. Hepatic phosphoenolpyruvate carboxykinase expression was suppressed, while hepatic glycogen content and phosphorylated Gsk-3β were significantly increased, in livers of fasted mice with increased Elovl5 activity. As such, hepatic Elovl5 activity may affect hepatic glucose production during fasting. In summary, Elovl5-induced changes in hepatic fatty acid content affect multiple pathways regulating hepatic lipid and carbohydrate composition. (Source: The Journal of Lipid Research)

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[research articles] control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Lipid transfer inhibitor protein (LTIP) is a physiologic regulator of cholesteryl ester transfer protein (CETP) function. We previously reported that LTIP activity is localized to LDL, consistent with its greater inhibitory activity on this lipoprotein. With a recently described immunoassay for LTIP, we investigated whether LTIP mass is similarly distributed. Plasma fractionated by gel filtration chromatography revealed two LTIP protein peaks, one coeluting with LDL, and another of ~470 kDa. The 470 kDa LTIP complex had a density of 1.134 g/ml, indicating ~50% lipid content, and contained apolipoprotein A-I. By mass spectrometry, partially purified 470 kDa LTIP also contains apolipoproteins C-II, D, E, J, and paraoxonase 1. Unlike LDL-associated LTIP, the 470 kDa LTIP complex does not inhibit CETP activity. In normolipidemic subjects, ~25% of LTIP is in the LDL-associated, active form. In hypercholesterolemia,this increases to 50%, suggesting that lipoprotein composition may influence the status of LTIP activity. Incubation (37°C) of normolipidemic plasma increased active, LDL-associated LTIP up to 3-fold at the expense of the inactive pool. Paraoxon inhibited this shift by 50%. Overall, these studies show that LTIP activity is controlled by its reversible incorporation into an inactive complex. This may provide for short-term fine-tuning of lipoprotein remodeling mediated by CETP. (Source: The Journal of Lipid Research)

[research articles] regulation of lipin-1 gene expression by glucocorticoids during adipogenesis

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. Lipin-1 expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor and CCAAT enhancer binding protein , and for the synthesis of triacylglycerol. The requirement of lipin-1 for adipocyte differentiation can be explained, in part, by its activity as the sole adipocyte phosphatidic acid phosphatase-1 enzyme, which converts phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol. Here we identify glucocorticoids as the stimulus for the induction of lipin-1 expression in differentiating adipocytes, and characterize a glucocorticoid response element (GRE) in the Lpin1 promoter. The Lpin1 GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays. This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting. (Source: The Journal of Lipid Research)

[research articles] accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

The pathogenesis of aortic valve stenosis (AS) is characterized by the accumulation of LDL-derived cholesterol in the diseased valves. Since LDL particles also contain plant sterols, we investigated whether plant sterols accumulate in aortic valve lesions. Serum samples were collected from 82 patients with severe AS and from 12 control subjects. Aortic valves were obtained from a subpopulation of 21 AS patients undergoing valve surgery and from 10 controls. Serum and valvular total cholesterol and noncholesterol sterols were measured by gas-liquid chromatography. Noncholesterol sterols, including both cholesterol precursors and sterols reflecting cholesterol absorption, were detected in serum samples and aortic valves. The higher the ratios to cholesterol of the cholesterol precursors and absorption markers in serum, the higher their ratios in the stenotic aortic valves (r = 0.74, P < 0.001 for lathosterol and r = 0.88, P < 0.001 for campesterol). The valvular ratio to cholesterol of lathosterol correlated negatively with the aortic valve area (r = –0.47, P = 0.045), suggesting attenuation of cholesterol synthesis with increasing severity of AS. The higher the absorption of cholesterol, the higher the plant sterol contents in stenotic aortic valves. These findings suggest that local accumulation of plant sterols and cholesterol precursors may participate in the pathobiology of aortic valve disease. (Source: The Journal of Lipid Research)

[research articles] candidate genes for plasma triglyceride, ffa, and glucose revealed from an intercross between inbred mouse strains nzb/b1nj and nzw/lacj

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

To identify the genes controlling plasma concentrations of triglycerides (TGs), FFAs, and glucose, we carried out a quantitative trait loci (QTL) analysis of the closely related mouse strains New Zealand Black (NZB/B1NJ) and New Zealand White (NZW/LacJ), which share 63% of their genomes. The NZB x NZW F2 progeny were genotyped and phenotyped to detect QTL, and then comparative genomics, bioinformatics, and sequencing were used to narrow the QTL and reduce the number of candidate genes. Triglyceride concentrations were linked to loci on chromosomes (Chr) 4, 7, 8, 10, and 18. FFA concentrations were affected by a significant locus on Chr 4, a suggestive locus on Chr 16, and two interacting loci on Chr 2 and 15. Plasma glucose concentrations were affected by QTL on Chr 2, 4, 7, 8, 10, 15, 17, and 18. Comparative genomics narrowed the QTL by 31% to 86%; haplotype analysis was usually able to further narrow it by 80%. We suggest several candidate genes: Gba2 on Chr 4, Irs2 on Chr 8, and Ppargc1b on Chr 18 for TG; A2bp1 on Chr 16 for FFA; and G6pc2 on Chr 2 and Timp3 on Chr 10 for glucose. (Source: The Journal of Lipid Research)

[research articles] alteration of retinal rod outer segment membrane fluidity in a rat model of smith-lemli-opitz syndrome

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Smith-Lemli-Opitz syndrome (SLOS) is caused by an inherited defect in the last step in cholesterol (Chol) biosynthesis, leading to abnormal accumulation of 7-dehydrocholesterol and decreased Chol levels. Progressive retinal degeneration occurs in an animal model of SLOS, induced by treating rats with AY9944, a selective inhibitor of the enzyme affected in SLOS. Here we evaluated alterations in the biochemical and physical properties of retinal rod outer segment (ROS) membranes in this animal model. At 1 month of AY9944 treatment, there were modest alterations in fatty acid composition, but no significant differences in cis-parinaric acid (cPA) spectroscopic parameters in ROS membranes from treated versus control rats. However, at 3 months, ROS docosahexaenoic acid (DHA) content was dramatically reduced, and cPA fluorescence anisotropy values were decreased, relative to controls. Also, 1,6-diphenyl-1,3,5-hexatriene exhibited decreased rotational motion and increased orientational order in ROS membranes from 3 month-old AY9944-treated rats, relative to controls. No significant changes in protein:lipid ratios were observed; however, rhodopsin regenerability was compromised by 3 months of treatment. These findings are consistent with reduced ROS membrane fluidity in the SLOS rat model, relative to controls, primarily due to the dramatic reduction in membrane DHA levels, rather than altered sterol composition. (Source: The Journal of Lipid Research)

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[research articles] decreased ipla2{gamma} expression induces lipid peroxidation and cell death and sensitizes cells to oxidant-induced apoptosis

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Our previous studies showed that renal proximal tubular cells (RPTC) express Ca2+-independent phospholipase A2 (iPLA2) in endoplasmic reticulum (ER) and mitochondria and that iPLA2 prevents and/or repairs lipid peroxidation induced by oxidative stress. Our present studies determined the importance of iPLA2 in mitochondrial and cell function using an iPLA2-specific small hairpin ribonucleic acid (shRNA) adenovirus. iPLA2 expression and activity were decreased in the ER by 24 h and in the mitochondria by 48 h compared with scrambled shRNA adenovirus-treated cells. Lipid peroxidation was elevated by 2-fold at 24 h and remained elevated through 72 h in cells with decreased iPLA2. Using electrospray ionization-mass spectrometry, primarily phosphatidylcholines and phosphatidylethanolamines were increased in iPLA2-shRNA-treated cells. At 48 h after exposure to the iPLA2 shRNA, uncoupled oxygen consumption was inhibited by 25% and apoptosis was observed at 72 and 96 h. RPTC with decreased iPLA2 expression underwent apoptosis when exposed to a nonlethal concentration of the oxidant tert-butyl hydroperoxide (TBHP). Exposure of control cells to a nonlethal concentration of TBHP induced iPLA2 expression in RPTC. These results suggest that iPLA2 is required for the prevention and repair of basal lipid peroxidation and the maintenance of mitochondrial function and viability, providing further evidence for a cytoprotective role for iPLA2 from oxidative stress. (Source: The Journal of Lipid Research)

[research articles] characterization of overall ceramide species in human stratum corneum

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Ceramides (CERs) in human stratum corneum (SC) play physicochemical roles in determining barrier and water-holding functions of the skin, and specific species might be closely related to the regulation of keratinization, together with other CER-related lipids. Structures of those diverse CER species, however, have not been comprehensively revealed. The aim of this study was to characterize overall CER species in the SC. First, we constructed 3D multi-mass chromatograms of the overall CER species, based on normal-phase liquid chromatography (NPLC) connected to electrospray ionization-mass spectrometry (ESI-MS) using a gradient elution system and a postcolumn addition of a volatile salt-containing polar solvent. The CERs targeted from the 3D chromatograms were structurally analyzed using NPLC-ESI-tandem mass spectrometry (MS/MS), which resulted in the identification of 342 CER species in the inner forearm SC. This led to the discovery of a new CER class consisting of -hydroxy fatty acid and dihydrosphingosine moieties, in addition to the 10 classes generally known. The results also revealed that those CERs contain long-chain (more than C18)-containing sphingoids and a great number of isobaric species. These novel results will contribute not only to physiochemical research on CERs in the SC but also to lipidomics approaches to CERs in the skin. (Source: The Journal of Lipid Research)

[research articles] inhibition of stearoyl coa desaturase activity induces hypercholesterolemia in the cholesterol-fed hamster

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Reduction of stearoyl CoA desaturase (SCD) activity has been shown to induce resistance to diet-induced obesity in mice. In the present study, SCD was inhibited by feeding sterculic oil (SO) to male Golden Syrian Hamsters fed high-fat diets with or without added dietary cholesterol. In the absence of cholesterol, SO had little impact on adipose tissue mass or plasma lipoprotein concentrations. When cholesterol was included in the diet, inhibition of SCD resulted in reduced body weight, adipose tissue mass, and feed efficiency. These animals also exhibited a marked hypercholesterolemia, with an accumulation of free-cholesterol–rich particles within the LDL density range, and reduced hepatic cholesterol esterification. This was accompanied by a 20-fold increase in plasma alanine aminotransferase, which was suggestive of significant hepatic damage. Hepatic acetyl CoA carboxylase and fatty acid synthase mRNA concentrations were reduced by feeding cholesterol and SO, whereas lipoprotein lipase and SCD mRNA were increased. These changes were associated with decreased hepatic sterol regulatory element binding protein 1a and 1c mRNA concentrations. Thus, inhibition of SCD activity in the cholesterol-fed hamster results in a reduction in overall body weight and adipose tissue deposition. However, this also causes marked hypercholesterolemia and potential liver damage. (Source: The Journal of Lipid Research)

[research articles] effects of trans mufa from dairy and industrial sources on muscle mitochondrial function and insulin sensitivity

The Journal of Lipid Research — Fri, 13 Jun 2008 04:00:00 +0100

Epidemiological studies suggest that chronic consumption of trans MUFA may alter muscle insulin sensitivity. The major sources of dietary trans MUFA (dairy fat vs. industrially hydrogenated oils) have different isomeric profiles and thus probably different metabolic consequences. These effects may involve alterations in muscle mitochondrial oxidative capacity, which may in turn promote insulin resistance if fatty acid oxidation is reduced. We report that in Wistar rats, an 8 week diet enriched (4% of energy intake) in either dairy, industrial, or control MUFA did not alter insulin and glucose responses to an intraperitoneal glucose tolerance test (1g/kg). In C2C12 myotubes, vaccenic and elaidic acids did not modify insulin sensitivity compared with oleic acid. Furthermore, the ex vivo total, mitochondrial and peroxisomal oxidation rates of [1-14C]oleic, vaccenic, and elaidic acids were similar in soleus and tibialis anterior rat muscle. Finally, an 8 week diet enriched in either dairy or industrial trans MUFA did not alter mitochondrial oxidative capacity in these two muscles compared with control MUFA but did induce a specific reduction in soleus mitochondrial ATP and superoxide anion production (P < 0.01 vs. control). In conclusion, dietary trans MUFA of dairy or industrial origin have similar effects and do not impair muscle mitochondrial capacity and insulin sensitivity. (Source: The Journal of Lipid Research)