Elevated Plasma Triacylglycerol Research Articles

Zinc finger 259 gene polymorphisms in Egyptian patients with metabolic syndrome and its association with dyslipidemia.

Zinc finger protein 1 (ZPR1), encoded by the ZNF259 gene, plays crucial roles in transcriptional regulation and cell cycle progression. Despite its known functions, its specific involvement in Metabolic Syndrome (MetS) remains debated. Genome-wide association studies have identified several genes, including ZNF259, implicated in lipid metabolism and associated with MetS. Single nucleotide polymorphisms (SNPs) in ZNF259 have been linked to altered lipid metabolism during the development of MetS. This study aims to investigate the association between MetS in Egyptian patients and three specific ZNF259 SNPs: rs964184, rs2075294, and rs2075290. The objective is to explore how these SNPs correlate with MetS development, other health outcomes, and their interaction with dyslipidemia biomarkers. 200 Egyptian participants were enrolled, and divided into two groups: 100 patients diagnosed with dyslipidemia and 100 healthy controls. The study involved comprehensive assessments, including lipid profile analysis, anthropometric measurements, and genotyping of rs964184, rs2075290, and rs2075294 in the ZNF259 gene using Real-Time Polymerase Chain Reaction (PCR). The findings indicate that rs964184 SNP correlates significantly with elevated plasma triacylglycerol (TG) levels, while rs2075290 and rs2075294 are associated with higher total serum cholesterol (TC) and TG levels. Among these SNPs, rs2075294 showed the highest predictive value (area under the curve of 0.748), followed by rs2075290 (0.738), and rs964184 (0.583), suggesting rs2075294 as the most influential SNP in MetS prediction. This study underscores the predictive role of ZNF259 SNPs in MetS risk among Egyptians. Future research should further explore the implications of ZNF259 in MetS pathogenesis and its potential as a biomarker for personalized health interventions.

Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.

Naked Mole-Rat, a Rodent with an Apolipoprotein A-I Dimer.

A variety of rodents have been used as experimental animals in metabolic studies of plasma lipids and lipoproteins. These studies have included understanding the functional role of apolipoprotein A-I, the major protein on the surface of HDL. Reviewing the genomic database for entries for rodent apoA-I genes, it was discovered that the naked mole-rat (Heterocephalus glaber) gene encoded a protein with a cysteine at residue 28. Previously, two cases have been reported in which human heterozygotes had apoA-I with cysteine at residues 173 (apoA-I Milano) or at 151 (apoA-I Paris). Interestingly, both groups, in spite of having low levels of HDL and moderately elevated plasma triacylglycerols, had no evidence of cardiovascular disease. Moreover, the presence of the cysteine enabled the apoA-I to form both homodimers and heterodimers. Prior to this report, no other mammalian apoA-I has been found with a cysteine in its sequence. In addition, the encoded naked mole-rat protein had different amino acids at sites that were conserved in all other mammals. These differences resulted in naked mole-rat apoA-I having an unexpected neutral pI value, whereas other mammalian apoA-I have negative pI values. To verify these sequence differences and to determine if the N-terminal location of C28 precluded dimer formation, we conducted mass spectrometry analyses of apoA-I and other proteins associated with HDL. Consistent with the genomic data, our analyses confirmed the presence of C28 and the formation of a homodimer. Analysis of plasma lipids surprisingly revealed a profile similar to the human heterozygotes.

Effects of Amino Acid Supplementation on Liver Lipid Content: A Randomized, Double-Blinded, Placebo-Controlled Trial

Abstract Objectives To test whether chronic ingestion of essential amino acids (EAAs) plus arginine lowers liver lipid content when compared with a placebo (non-essential amino acids; NEAAs). Methods Older adults (50–75 y) with elevated fasting plasma triacylglycerol (TAG) concentrations were recruited into the study. After screening (week -2), all participants ingested placebo (NEAAs; alanine, aspartic acid, and serine) capsules twice daily (between meals) for two weeks and 3 T nuclear magnetic resonance spectroscopy scans were used to determine baseline (week 0) liver lipid percentage. Participants were then randomised to receive capsules containing 11 g of EAAs plus arginine (n = 10) or NEAAs (n = 9) twice daily for eight weeks, using a double-blinded design. Follow-up NMR spectroscopy scans were conducted at eight weeks after the onset of randomised supplementation (week 8) to determine the impact on liver lipids. Results Liver lipid percentage (mean ± standard deviation) was not significantly altered by randomised supplementation in either the EAAs plus arginine group (Pre: 9.08 ± 7.90%; Post: 8.94 ± 6.91%; P = 0.65) or the NEAAs group (Pre: 10.23 ± 7.20%; Post: 9.65 ± 7.70%; P = 0.18). Change in fasting plasma TAG during placebo run-in (Week 0 minus screening) was significantly negatively correlated with change in liver lipid content (week 8 minus week 0) for the EAAs plus arginine group (r = −0.722; P = 0.02), but not for the NEAAs group A (r = −0.479; P = 0.19). Conclusions Eight weeks of essential amino acids plus arginine ingestion did not significantly lower liver lipid content in older adults. However, ingestion of non-essential amino acids during the run-in period may have influenced the effect on liver fat of subsequent randomised amino acid supplementation, suggesting further investigation is warranted. Funding Sources The study was sponsored by NIH/NIA (award to EB), and the Roy and Christine Sturgis Charitable Trust (award to NMH). Screenings and study visits were undertaken within the ITS-Clinical Research Center at UTMB, funded by NIH/NCRR, and within the UAMS Donald W. Reynolds Institute on Aging at UAMS, funded by NIH/NIA. NMH and EB were also funded by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000.

Effects of triacylglycerol on the structural remodeling of human plasma very low- and low-density lipoproteins

Very low-density lipoprotein (VLDL) is the main plasma carrier of triacylglycerol that is elevated in pathological conditions such as diabetes, metabolic syndrome, obesity and dyslipidemia. How variations in triacylglycerol levels influence structural stability and remodeling of VLDL and its metabolic product, low-density lipoproteins (LDL), is unknown. We applied a biochemical and biophysical approach using lipoprotein remodeling by lipoprotein lipase and cholesterol ester transfer protein, along with thermal denaturation that mimics key aspects of lipoprotein remodeling in vivo. The results revealed that increasing the triacylglycerol content in VLDL promotes changes in the lipoprotein size and release of the exchangeable apolipoproteins. Similarly, increased triacylglycerol content in LDL promotes lipoprotein remodeling and fusion. These effects were observed in single-donor lipoproteins from healthy subjects enriched in exogenous triolein, in single-donor lipoproteins from healthy subjects with naturally occurring differences in endogenous triacylglycerol, and in LDL and VLDL from pooled plasma of diabetic and normolipidemic patients. Consequently, triacylglycerol-induced destabilization is a general property of plasma lipoproteins. This destabilization reflects a direct effect of triacylglycerol on lipoproteins. Moreover, we show that TG can act indirectly by increasing lipoprotein susceptibility to oxidation and lipolysis and thereby promoting the generation of free fatty acids that augment fusion. These in vitro findings are relevant to lipoprotein remodeling and fusion in vivo. In fact, fusion of LDL and VLDL enhances their retention in the arterial wall and, according to the response-to-retention hypothesis, triggers atherosclerosis. Therefore, enhanced fusion of triacylglycerol-rich lipoproteins suggests a new causative link between elevated plasma triacylglycerol and atherosclerosis.

Antihyperlipidemic and antioxidant activities of the ethanolic extract of Garcinia cambogia on high fat diet-fed rats.

The study investigated the antihyperlipidemic and antioxidant activities of the ethanolic extract of Garcinia cambogia on high fat diet-fed rats. The phytochemical constituents, total polyphenol content and ferric reducing antioxidant power (FRAP) were estimated in the G. cambogia extract (GE). Male Wistar rats were fed with either standard rodent diet or 30% high-fat diet and administered with GE at a dose of 400 mg/kg body weight/day for 10 weeks. At the end, lipid profile and oxidative stress parameters were estimated. The analyses revealed the presence of carbohydrates, proteins, sterols, tannins, flavonoids and saponins in GE. The total polyphenol content and FRAP of GE were 82.82±7.64 mg of gallic acid equivalents and 260.49±10.18 µM FRAP per gram of the GE. High-fat feeding elevated plasma total cholesterol (TC), triacylglycerol (TAG), non-high-density lipoprotein-cholesterol (non-HDL-C), malondialdehyde (MDA), reduced HDL-C and blood antioxidants, glutathione (GSH), glutathione peroxidase (GPx), catalase. Increase in total oxidant status (TOS), oxidative stress index (OSI) and decrease in the total antioxidant status (TAS) were observed in plasma, liver and kidney of fat-fed rats. Administration of GE decreased food intake, plasma TC, TAG, non HDL-C, MDA, increased HDL-C and blood antioxidants GSH, GPx, catalase. GE also reduced TOS, OSI and elevated TAS in plasma and liver of fat-fed rats. Renal OSI was significantly reduced upon GE treatment. Our study demonstrated that GE is effective in ameliorating high-fat-diet-induced hyperlipidemia and oxidative stress.

Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.

Apolipoprotein (apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol (TG) homeostasis. Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipo­protein lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of car­diovascular disease. Single nucleotide polymorphisms (SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction. Genetically engineered mouse mod­els and human population studies suggest that, in certain instances, supplementation with wild type (WT) apoA-V may have therapeutic benefit. It is hypothesized that individuals that manifest elevated plasma TG owing to deleter­ious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance. On the other hand, subjects with hypertriglyceridemia of independent origin (unrelated to apoA-V func­tion) may not respond to apoA-V augmentation in this manner. Improvement in the ability to identify individuals predicted to benefit, advances in gene transfer technology and the strong connection between HTG and heart disease, point to apoA-V supplementation as a viable disease prevention / therapeutic strategy. Candidates would include individuals that manifest chronic TG elevation, have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels.

Intestinal acyl-CoA:diacylglycerol acyltransferase 2 overexpression enhances postprandial triglyceridemic response and exacerbates high fat diet-induced hepatic triacylglycerol storage

Intestinal acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) is important in the cellular and physiological responses to dietary fat. To determine the effect of increased intestinal DGAT2 on cellular and physiological responses to acute and chronic dietary fat challenges, we generated mice with intestine-specific overexpression of DGAT2 and compared them with intestine-specific overexpression of DGAT1 and wild-type (WT) mice. We found that when intestinal DGAT2 is present in excess, triacylglycerol (TG) secretion from enterocytes is enhanced compared to WT mice; however, TG storage within enterocytes is similar compared to WT mice. We found that when intestinal DGAT2 is present in excess, mRNA levels of genes involved in fatty acid oxidation were reduced. This result suggests that reduced fatty acid oxidation may contribute to increased TG secretion by overexpression of DGAT2 in intestine. Furthermore, this enhanced supply of TG for secretion in Dgat2Int mice may be a significant contributing factor to the elevated fasting plasma TG and exacerbated hepatic TG storage in response to a chronic HFD. These results highlight that altering fatty acid and TG metabolism within enterocytes has the capacity to alter systemic delivery of dietary fat and may serve as an effective target for preventing and treating metabolic diseases such as hepatic steatosis.

Influence of apolipoprotein A-V on the metabolic fate of triacylglycerol

Apolipoprotein (apo) A-V functions to modulate intracellular and extracellular triacylglycerol metabolism. The present review addresses molecular mechanisms underlying these effects. The relevance of apoA-V to human disease conditions is illustrated by the strong correlation between single nucleotide polymorphisms in APOA5, elevated plasma triacylglycerol and dyslipidemic disease. Despite undergoing processing for secretion from hepatocytes, a portion of apoA-V escapes this destiny and accumulates as a component of cytosolic lipid droplets. Expression of recombinant apoA-V in hepatocarcinoma cells results in increased lipid droplet size and number at the expense of triacylglycerol secretion.ApoA-V modulates atherosclerosis in hypercholesterolemic apoE null mice. ApoE null/human apoA-V transgenic mice had reduced levels of triacylglycerol and cholesterol in plasma along with decreased aortic lesion size. ApoA-V modulates triacylglycerol metabolic fate. Following its synthesis, apoA-V enters the endoplasmic reticulum and associates with membrane defects created by triacylglycerol accumulation. Association of apoA-V with endoplasmic reticulum membrane defects promotes nascent lipid droplets budding toward the cytosol. Despite its low concentration in plasma (∼150 ng/ml), apoA-V modulates lipoprotein metabolism by binding to glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1. This interaction effectively localizes triacylglycerol-rich lipoproteins in the vicinity of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein1's other ligand, lipoprotein lipase.

Relationship between hepatic steatosis progression and cardiovascular performance under chronic nutritional overload

To evaluate whether hepatic steatosis progression might be a risk factor for cardiovascular performance alteration under chronic nutritional overload. Male Wistar rats were divided to receive chow diet (C) or high‐fat diet plus sugar (300g/L of water) (H) for 6, 12 and 24 weeks. Adiposity index and hepatic and plasma triacylglycerol (TG) as well as free fatty acid (FFA) concentration were evaluated. Hepatic steatosis was analyzed by H&E staining. Cardiovascular performance was analyzed by a two‐dimensional echocardiography. Two‐Way ANOVA and post hoc Tukey test were used. The nutritional overload significantly increased adiposity index in all three experimental times in H group compared to C. The higher adipose tissue was associated with elevated plasma TG levels, while plasma FFA was influenced just with long‐term of obesity. The nutritional overload resulted in a time‐dependent hepatic steatosis progression in H group. Hepatic TG and FFA concentration was elevated in H group than C group in all moments. These metabolic changes in the livers did not result in any dysregulation of cardiac morphology and function. In conclusion, chronic nutritional overload induced and promoted hepatic steatosis progression. However, this metabolic scenario did not alter cardiovascular performance evaluated by in vivo two dimensional echocardiography. Supported by FAPESP: 2011/21664–9 and 2011/09945–2

Carboxylesterase1/Esterase-x Regulates Chylomicron Production in Mice

Elevated postprandial plasma triacylglycerol (TG) concentrations are commonly associated with obesity and the risk of cardiovascular disease. Dietary fat contributes to this condition through the production of chylomicrons. Carboxylesterases have been mainly studied for their role in drug metabolism, but recently they have been shown to participate in lipid metabolism; however, their role in intestinal lipid metabolism is unknown. Carboxylesterase1/esterase-x (Ces1/Es-x) deficient mice become obese, hyperlipidemic and develop hepatic steatosis even on standard chow diet. Here, we aimed to explore the role of Ces1/Es-x in intestinal lipid metabolism. Six-month old wild-type and Ces1/Es-x deficient mice were maintained on chow diet and intestinal lipid metabolism and plasma chylomicron clearance were analyzed. Along the intestine Ces1/Es-x protein is expressed only in proximal jejunum. Ablation of Ces1/Es-x expression results in postprandial hyperlipidemia due to increased secretion of chylomicrons. The secreted chylomicrons have aberrant protein composition, which results in their reduced clearance. In conclusion, Ces1/Es-x participates in the regulation of chylomicron assembly and secretion. Ces1/Es-x might act as a lipid sensor in enterocytes regulating chylomicron secretion rate. Ces1/Es-x might represent an attractive pharmacological target for the treatment of lipid abnormalities associated with obesity, insulin resistance and fatty liver disease.

Quality assessment and anti-obesity activity of Stellaria media (Linn.) Vill

BackgroundObesity is recognized as a social problem, associated with serious health risks and increased mortality. Numerous trials have been conducted to find and develop new anti-obesity drugs through herbal sources to minimize side effects associated with the present anti-obesity drugs. The present study was designed to evaluate the quality control parameters, quantitative phytochemical analysis (total phenolic, total flavonoids and total saponin content), and the anti-obesity effect of lyophilized juice (LJ) of Stellaria media (Linn.) Vill. by employing in vitro and in vivo models.MethodsIn vitro studies were performed to evaluate the inhibitory activity of LJ on pancreatic amylase and lipase. The in vivo pancreatic lipase activity was evaluated by measurement of plasma triacylglycerol levels after oral administration of lipid emulsion to swiss albino mice. Furthermore, the anti-obesity effect of LJ was assessed at two doses, 400 mg/kg and 900 mg/kg body weight in mice fed a high-fat-diet with or without LJ for 6 weeks.ResultsThe LJ inhibited pancreatic amylase and lipase activity in vitro and elevated plasma triacylglycerol level in mice. LJ suppressed the increase in body weight, retroperitoneal adipose tissue, liver weights and serum parameters viz., total cholesterol, total triglyceride, LDL-cholesterol level at the dose of 900 mg/kg body weight of the mice fed with high fat diet. The total phenolic, flavonoid and saponin contents were found to be 0.26 mg/g, 1.4 mg/g and 1.19 μg/g respectively of LJ.ConclusionThe anti-obesity effects of LJ in high-fat-diet fed mice may be partly mediated through delaying the intestinal absorption of dietary fat and carbohydrate by inhibiting digestive enzymes.

Influence of maternal nutrition on the metabolic syndrome and cardiovascular risk in the offspring

Human epidemiological evidence and experiments using animal models have clearly indicated that maternal diet can have a significant impact on the life-long susceptibility of offspring to chronic disease. This includes many of the traits (obesity, insulin resistance, elevated plasma triacylglycerol and hypertension) associated with the metabolic syndrome. Evidence is presented that both maternal undernutrition and overnutrition are associated with such ‘fetal programming’. Metabolic syndrome is associated with an increased risk of developing cardiovascular disease and recent evidence is emerging to suggest that maternal nutrition impacts on the development of atherosclerosis in the offspring. Epigenetic mechanisms, such as changes in DNA methylation, that result in lifelong changes in gene expression, appear to be at least one of the underlying mechanisms of such fetal programming.

Effects of altering the ratio of dietary n−6 to n−3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45–70 y: the OPTILIP Study

Insulin resistance is associated with elevated plasma triacylglycerol, low HDL concentrations, elevated postprandial lipemia, and a predominance of small, dense LDLs (sdLDLs). It has been hypothesized that the dietary ratio of n-6 to n-3 (n-6:n-3) polyunsaturated fatty acids (PUFAs) may have favorable effects on these risk factors by increasing insulin sensitivity. The objective was to measure changes in insulin sensitivity, lipoprotein size, and postprandial lipemia after a 6-mo alteration in n-6:n-3. In a randomized, parallel design in 258 subjects aged 45-70 y, we compared 4 diets providing 6% of energy as PUFAs with an n-6:n-3 between 5:1 and 3:1 with a control diet that had an n-6:n-3 of 10:1. The diets were enriched in alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or both. Insulin sensitivity was assessed with the homeostatic model assessment of insulin resistance and the revised quantitative insulin sensitivity test. Dietary intervention did not influence insulin sensitivity or postprandial lipase activities. Fasting and postprandial triacylglycerol concentrations were lower, and the proportion of sdLDLs decreased (by 12.7%; 95% CI: -22.9%, 2.4%), with an n-6:n-3 of approximately 3:1, which was achieved by the addition of long-chain n-3 PUFAs (EPA and DHA). Decreasing the n-6:n-3 does not influence insulin sensitivity or lipase activities in older subjects. The reduction in plasma triacylglycerol after an increased intake of n-3 long-chain PUFAs results in favorable changes in LDL size.

Does maternal dietary mineral restriction per se predispose the offspring to insulin resistance?

Maternal undernutrition is hypothesized to predispose the offspring to disease in adult life. The relevance of maternal macronutrient deficiency has been well studied but not that of micronutrients. To assess the effect of maternal dietary mineral restriction per se on oral glucose tolerance (OGT), insulin resistance (IR) and fat metabolism in offspring. Female weanling Wistar/NIN rats received a control or a 50% mineral-restricted (MR) diet for 12 weeks, by which time MR rats had lower plasma Fe, Zn, Mg and Ca concentrations. Following mating with control males, a third of the MR dams were shifted to the control diet from parturition. Half of the pups born to the remaining MR dams were weaned onto the control diet while the other half continued on the MR diet. Pregnant MR dams had a higher abortion rate, body weights of their pups at birth and weaning were lower and rehabilitation had no beneficial effect. No offspring had impaired OGT, and IR status was comparable among different groups on postnatal days 40, 70, 100 or 180. Compared with controls, total body electrical conductivity measurements indicated significantly higher body fat %, lower lean body mass and fat-free mass in MR offspring besides elevated plasma triacylglycerols. Mineral rehabilitation from parturition or weaning had little effect on these changes, which did not appear to be due to increased oxidative stress. Maternal MR per se resulted in an increase in body fat and in plasma triacylglycerol concentrations in the offspring. These changes had, however, no discernable effect on insulin sensitivity over the first 180 days of life.

Insulin resistance—associated cardiovascular disease: potential benefits of conjugated linoleic acid

Type 2 diabetes and associated cardiovascular disease have reached global epidemic proportions. Recent data from the World Health Organization Multinational Study of Vascular Disease in Diabetes indicate that cardiovascular disease is the leading cause of mortality (52% of deaths) in individuals with type 2 diabetes. Although insulin resistance plays a critical role in the pathogenesis of type 2 diabetes-related cardiovascular disease, other related risk factors often cluster in a single patient; the combination of insulin resistance and these risk factors is known as the metabolic syndrome. According to the World Health Organization definition, this constellation of risk factors includes hypertension, elevated plasma triacylglycerol, reduced HDL cholesterol, central obesity, and microalbuminuria. The Multiple Risk Factor Intervention Trial showed that, although diabetes or insulin resistance is an independent risk factor for cardiovascular disease mortality, these other components of the metabolic syndrome confer additive risk. Thus, to effectively address cardiovascular disease in persons with diabetes, intervention would ideally target all these factors. Conjugated linoleic acid could represent a candidate agent. The therapeutic potential of conjugated linoleic acid against insulin resistance-associated cardiovascular disease is discussed on the basis of the reported effects of conjugated linoleic acid on individual components of the metabolic syndrome.

Postprandial variations in fibrinolytic activity in middle-aged men are modulated by plasminogen activator inhibitor I 4G-675/5G genotype but not by the fat content of a meal

Decreased fibrinolytic activity is associated with an increased risk of ischemic heart disease and elevated plasma triacylglycerol concentrations. The goal was to determine whether plasminogen activator inhibitor 1 (PAI-1) and fibrinolytic activities are influenced by 1) dietary fat intake from a test meal and 2) the PAI-1 4G allele. A parallel randomized controlled trial was used to compare the effect on fibrinolytic activity, measured as dilute clot lysis time, of high-oleate or high-palmitate test meals (both containing 50 g fat; both n = 18) with that of a low-fat test meal (15 g fat; n = 15) in men aged > 52 y. In a second study, postprandial changes in PAI-1 activity were measured in 32 men in response to a high-oleate meal containing 50 g fat. The results from both studies were analyzed according to PAI-1 4G-675/5G genotype. Fasting dilute clot lysis time was positively associated with body mass index (r = 0.326, P = 0.02) and was shortened postprandially (P < 0.00001) independent of the fat content of the meal. Fasting PAI-1 activity was higher in those carrying the 4G allele and was correlated with fasting plasma triacylglycerol concentrations (r = 0.48, P = 0.008) and factor VII coagulant activity (r = 0.46, P = 0.012) after adjustments for age, body mass index, and genotype. Plasma PAI-1 activity decreased significantly after a meal but was not associated with postprandial changes in plasma triacylglycerols after a high-fat meal. The postprandial increase in plasma triacylglycerols was higher in subjects carrying the 4G allele. Fibrinolytic activity is not lower after meals rich in palmitate or oleate than after a low-fat meal.

Associations of low density lipoprotein particle composition with atherogenicity.

A growing body of data suggests that in addition to LDL-cholesterol concentrations, compositional properties of LDL, including size and fatty acid composition, are important in determining the relative degree of atherogenicity. This review examines current research in this field to evaluate which properties of LDL may most directly influence the risk of coronary heart disease. The presence of small dense LDL has been correlated with an increased risk of coronary heart disease, but this has not been shown to be fully independent of related factors such as elevated plasma triacylglycerol concentrations. An increased susceptibility of small dense LDL to in-vitro oxidation has also been demonstrated, but its importance to coronary heart disease risk has not been established. Other studies have found that the presence of enlarged LDL, modified (oleate enriched) fatty acyl composition of LDL, and higher numbers of LDL particles in plasma also are endpoints associated with an increased risk of coronary heart disease. LDL size may indicate a metabolic condition associated with increased CHD risk as opposed to the direct promotion of atherosclerosis by specific particle types of LDL. In most claims of detrimental effects of small dense LDL, neither LDL particle concentrations nor the fatty acid composition of the particles were established, both factors being important in contributing to the atherogenic potential of LDL. The predisposition to premature coronary heart disease cannot currently be objectively assigned to any one type of LDL particle.

Postprandial lipaemia in familial combined hyperlipidaemia.

FCHL (familial combined hyperlipidaemia) is the most frequent inherited disorder of lipid metabolism leading to premature atherosclerosis. The usual phenotype in FCHL is elevated fasting plasma triacylglycerols, low HDL (high-density lipoprotein)-cholesterol concentrations and elevated plasma apolipoprotein B concentrations. The metabolic basis for this phenotype is hepatic overproduction of VLDL (very-low-density lipoprotein), which is only partly linked to the insulin resistance associated with FCHL. At this stage the molecular basis for this VLDL overproduction is not known, but emerging evidence points to a disturbed trapping of peripheral fatty acids, resulting in enhanced hepatic flux of NEFA [non-esterified ('free') fatty acids]. Postprandial hyperlipidaemia with accumulation of lipoprotein remnants and NEFA have been implicated in the development of atherosclerosis in this disorder. It has been proposed that, by VLDL overproduction, fasting hypertriglyceridaemia may lead to 'overflow' of the catabolic cascade for triacylglycerol-rich particles, thereby explaining the delayed catabolism of remnants in FCHL. Delayed clearance of remnants of VLDL and chylomicrons leads to enhanced interaction of these highly atherogenic particles with the endothelium, and enhanced trans-endothelial migration of the particles, resulting in a chronic inflammatory response that is the initiation of the atherosclerotic lesion. In this process, activated leucocytes (either directly by the remnants or indirectly by released NEFA) play an important role by adherence to the endothelium and migration into the subendothelial space, where the uptake of atherogenic remnants results in a vicious cycle of activation of endothelium, leucocytes and production of cytokines.

Metabolic markers following beta-adrenoceptor agonist infusion in footshock-stressed rats.

Stress hormones can alter metabolic functions in adipose tissue and liver, as well as the sensitivity of rat white adipocytes and rat atrial responses to beta-adrenergic agonists. In this study, we examined the effects of three daily footshock stress sessions on the plasma corticosterone, glucose, glycerol and triacylglycerol levels of fed, conscious male rats, and on the plasma glucose, glycerol and triacylglycerol levels of the same rats following iv infusions of beta-adrenergic agonists (isoproterenol: 0.4 nmol kg-1 min-1, noradrenaline: 5.0 microg kg-1 day-1, and BRL 37344 ([+/-]-[4-(2-[(2-[3-chlorophenyl]-2-hydroxyethyl)amino]propyl)phenoxy]acetic acid), a selective beta3-adrenoceptor agonist: 0.4 nmol kg-1 min-1). Plasma corticosterone levels increased significantly after each stress session, while triacylglycerol levels increased after the first session and glucose increased after the second and third sessions. Glycerol levels were unaltered after stress. These results suggest that repeated footshock stress may induce a metabolic shift from triacylglycerol biosynthesis to glucose release by hepatic tissue, with glycerol serving as one of the substrates in both pathways. Stressed rats were more sensitive to infusion of noradrenaline plus prazosin and to infusion of isoproterenol, with elevated plasma glucose, glycerol and triacylglycerol levels. The higher sensitivity of stressed rats to isoproterenol and noradrenaline was probably related to the permissive effect of plasma corticosterone. Only BRL 37344 increased plasma glycerol levels in stressed rats, probably because beta3-adrenoceptors are not involved in hepatic triacylglycerol synthesis, thus allowing glycerol to accumulate in plasma.