Plasma High-density Lipoprotein Cholesterol Concentrations Research Articles

Contribution of Genetic and Metabolic Syndrome to Omental Adipose Tissue PAI-1 Gene mRNA and Plasma Levels in Obesity

Plasminogen activator inhibitor type-1 (PAI-1) has already been associated with atherosclerosis; myocardial infarction; and cardiovascular disease risk factors such as obesity, insulin resistance, and dyslipidemia. However, factors regulating PAI-1 adipose tissue (AT) gene expression and plasma levels are not yet well defined. This study aims to assess the contribution of PAI-1 omental AT mRNA levels and genetic and metabolic factors to variation in plasma PAI-1 concentrations. Ninety-one non-diabetic premenopausal severely obese women (body mass index, BMI >35 kg/m(2)) undergoing bariatric surgery were phenotyped (fasting plasma glucose, lipid-lipoprotein, and PAI-1 levels) and genotyped for four PAI-1 polymorphisms. Omental AT PAI-1 mRNA levels were determined using real-time polymerase chain reaction. Stepwise regression analysis was used to identify independent PAI-1 AT mRNA and plasma level predictors. Among the variables included to the stepwise regression analysis, plasma high-density lipoprotein (HDL)-cholesterol (r = 0.38; p = 0.0004) and total cholesterol (r = 0.16; p = 0.0541) levels were the only two (out of 12) independent variables retained as predictive of PAI-1 omental AT mRNA levels, whereas BMI (r = 0.35; p = 0.0039), plasma HDL-cholesterol concentrations (r = -0.31; p = 0.0375), PAI-1 omental AT mRNA levels (r = 0.19; p = 0.0532) and PAI-1-844G/A (p = 0.0023), and rs6092 (p.A15T; p = 0.0358) polymorphisms contributed independently to plasma PAI-1 concentrations. Taken together, these variables explained 17.8% and 31.0% of the variability in PAI-1 AT mRNA and plasma levels, respectively. These results suggest that PAI-1 polymorphisms contribute significantly to PAI-1 plasma levels but do not support the notion that omental AT is one of its major source.

Modulatory Effect of Psidium Guajava Linn and Ocimum Gratissimum Linn on Lipid Profile and Selected Biochemical Indices in Rabbits Fed High Cholesterol Diet

The effect of aqueous leaf extracts of Psidium guajava(PG) and Ocimum gratissimum(OG) on fasting plasma glucose (FPG), total protein (TP), albumin (ALB), globulin (GLB), total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL), LDL-cholesterol (LDL) and lactate dehydrogenase (LDH) concentrations in rabbits fed high-cholesterol diet was investigated. Four groups of animals were used (n = 6). Animals in group A were fed normal laboratory pellet and water ad libitum; those in group B were fed the high-cholesterol diet (normal diet + 1% w/w cholesterol + 1% w/w vegetable oil) while those in groups C and D received a daily oral administration of 250 mg/kg body weight of the extract of Psidium guajava and Ocimum gratissimum, respectively, in addition to the high-cholesterol diet for a period of six weeks. Hypercholesterolemia, associated with hyperglycemia was induced significantly in animals in group B compared to normal control group (A) (P<0.01). There were also significant increases in the levels of LDL (P<0.05) and HDL (P<0.01). Treatments with PG and OG reduced the plasma cholesterol level by 15% and 28%, respectively, compared to animals in Group B. PG caused a remarkable increase in HDL (69%) but a decrease in LDL (74%) levels. OG on the other hand reduced the levels of both HDL and LDL by 50% and 26%, respectively, compared to animals in Group B. While the level of HDL in the OG group was similar to that of normal controls, the LDL level was significantly higher (71%). Furthermore, both extracts reduced the associated hyperglycemia significantly (P<0.05). This decrease was more pronounced in PG treated rabbits (PG; 43%, OG; 19%). In addition, OG stimulated a significant increase in the concentrations of LDH and serum protein, particularly albumin. These results show that aqueous extracts of both plants especially PG ameliorated the hypercholesterolemic and associated hyperglycemic effects of high cholesterol diet. However, OG shows possible contraindications and the safety of its ethnomedical usage warrants further investigation.

Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome

Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD.

Fasting cholesteryl ester transfer protein concentration is independently associated with the postprandial decrease in high-density lipoprotein cholesterol concentration after fat-rich meals: the Hoorn prandial study

The aim of the study was to test whether fasting or postprandial cholesteryl ester transfer protein (CETP) concentrations are associated with postprandial changes in high-density lipoprotein cholesterol (HDL-c) concentrations after fat-rich or carbohydrate-rich meals. Postmenopausal women (76 with normal glucose metabolism [NGM], 41 with type 2 diabetes mellitus [T2DM], and 38 T2DM women with statin therapy [T2DM-ST]) received 2 consecutive fat-rich or carbohydrate-rich meals on separate occasions. Linear regression analysis was performed to assess the associations of fasting CETP and postprandial changes of CETP with postprandial changes in HDL-c. Mean plasma HDL-c concentrations decreased significantly after the fat-rich meals: 0.18 ± 0.09 mmol/L in NGM, 0.16 ± 0.09 mmol/L in T2DM, and 0.14 ± 0.08 mmol/L in T2DM-ST women. This effect was smaller after using carbohydrate-rich meals: 0.12 ± 0.09 mmol/L in the NGM, 0.12 ± 0.08 mmol/L in the T2DM, and 0.10 ± 0.05 mmol/L in the T2DM-ST study group. Higher fasting but not postprandial CETP concentrations were associated with a larger postprandial decrease in HDL-c ( β −0.034; 95% confidence interval, −0.067 to −0.001) after the fat-rich meals. This association was independent of the postprandial increase in triglycerides and similar among the 3 study groups. A high fasting CETP concentration may contribute to the postprandial atherogenic lipoprotein profile in postmenopausal women by decreasing HDL-c after fat-rich meals. This effect is independent from the postprandial increase in triglycerides.

Evidence for the Thr79Met polymorphism of the ileal fatty acid binding protein (FABP6) to be associated with type 2 diabetes in obese individuals

The ileal fatty acid binding protein (FABP6) is known to be involved in enterohepatic bile acid metabolism. We have previously found a significant association between the rare allele of the FABP6 Thr79Met polymorphism and lower type 2 diabetes risk in a small case–control study (192 cases and 384 controls) embedded in the large EPIC-Potsdam cohort. A priori functional implication of the amino acid change was gained from in-silico analysis. In this study, we analysed an independent nested case–cohort including 543 incident type 2 diabetes cases from the EPIC-Potsdam cohort and a case–control study including 939 type 2 diabetes cases from KORA to confirm the association with type 2 diabetes and performed association analyses with quantitative disease-related measures in 2112 non-diabetic individuals. Homozygosity for the Met-allele was associated with lower risk of type 2 diabetes (EPIC-Potsdam: 0.70, P = 0.04; KORA: 0.79, P = 0.06) if adjusted for age, sex, body mass index (BMI), and waist circumference. The homozygous rare variant showed a significant interaction ( P = 0.006) with BMI. Relative risks in different categories (BMI <25, 25–30, and >30 kg/m 2) showed an association exclusively in obese (BMI >30 kg/m 2) individuals (combined risk ratio: 0.62, 95% CI 0.45–0.86). In non-diabetic individuals from the general adult population, no significant associations were observed with plasma total cholesterol, LDL-, and HDL-cholesterol, triglyceride, insulin and glucose concentration. In summary, we found evidence that the—putative functional—Thr79Met substitution of FABP6 confers a protective effect on type 2 diabetes in obese individuals.

Dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), alters plasma high-density lipoprotein-cholesterol levels and hepatic gene expression in rats

The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity.

Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

Fasting and Nonfasting LDL Cholesterol: To Measure or Calculate?

Whether lipid profiles should be measured in the fasting or nonfasting state is a hot topic (1)(2). The fasting state is that used conventionally (3)(4); however, it would be much simpler for patients worldwide if a lipid profile could be taken at any time of the day, irrespective of the time since and the content of the last meal. In both the US and Europe, LDL cholesterol is currently considered the most important measurement in a lipid profile (3)(5). Direct assays for measuring LDL cholesterol are widely available and used in many laboratories; however, even if LDL cholesterol measured with a direct method gives results similar to those calculated with the Friedewald equation, it is unclear how the 2 measurements compare in predicting ischemic cardiovascular disease. In this issue of Clinical Chemistry , Mora et al. report on an evaluation of fasting LDL cholesterol concentrations calculated with the Friedewald equation vs direct measurement of fasting and nonfasting LDL cholesterol concentrations for predicting cardiovascular disease in a prospective study of 27 331 women from the Women’s Health Study (6). They also examined misclassification of individuals into the National Cholesterol Education Program risk categories (3) with direct measurement of LDL cholesterol, compared with conventional Friedewald calculation of LDL cholesterol. These topics are timely and important. In 1972, Friedewald, Levy, and Fredrickson presented a new method for estimating LDL cholesterol and compared it with the gold standard of preparative ultracentrifugation (7). The method required only the measurement of plasma total cholesterol, HDL cholesterol, and triglyceride concentrations—all of which can be measured without the use of laborious and expensive …

The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis

Reverse cholesterol transport (RCT) is a term used to describe the efflux of excess cellular cholesterol from peripheral tissues and its return to the liver for excretion in the bile and ultimately the feces. It is believed to be a critical mechanism by which HDL exert a protective effect on the development of atherosclerosis. In this paradigm, cholesterol is effluxed from arterial macrophages to extracellular HDL-based acceptors through the action of transporters such as ABCA1 and ABCG1. After efflux to HDL, cholesterol may be esterified in the plasma by the enzyme lecithin:cholesterol acyltransferase and is ultimately transported from HDL to the liver, either directly via the scavenger receptor BI or after transfer to apolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein. Methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process and suggest that the dynamic rate of macrophage RCT is more strongly associated with atherosclerosis than the steady-state plasma concentration of HDL cholesterol. Promotion of macrophage RCT is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease, but robust measures of RCT in humans will be needed in order to confidently advance RCT-promoting therapies in clinical development.

Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.

The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

Low HDL-cholesterol (HDL-C) is associated with an increased risk for atherosclerosis, and concentrations are modulated by genetic factors and environmental factors such as smoking. Our objective was to assess whether the association of common single-nucleotide polymorphisms (SNPs) at ABCG5/G8 (i18429G>A, i7892T>C, Gln604GluC>G, 5U145A>C, Tyr54CysA>G, Asp19HisG>C, i14222A>G, and Thr400LysC>A) genes with HDL-C differs according to smoking habit. ABCG5/G8 SNPs were genotyped in 845 participants (243 men and 602 women). ABCG5/G8 (i7892T>C, 5U145A>C, Tyr54CysA>G, Thr400LysC>A) SNPs were significantly associated with HDL-C concentrations (P < 0.001-0.013) by which carriers of the minor alleles at the aforementioned polymorphisms and homozygotes for the Thr400 allele displayed lower HDL-C. A significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5/G8 (Gln604GluC>G, Asp19HisG>C, i14222A>G) SNPs displayed lower concentrations of HDL-C only if they were smokers (P = 0.001-0.025). Also, for ABCG8_Thr400LysC>A SNP, smokers, but not nonsmokers, homozygous for the Thr400 allele displayed lower HDL-C (P = 0.004). Further analyses supported a significant haplotype global effect on lowering HDL-C (P = 0.002) among smokers. In conclusion, ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers.

A Gene-Centric Approach to Elucidating Cardiovascular Risk

Although behavioral precedents including diet and cigarette smoking play an important role, coronary artery disease (CAD) exhibits significant heritability,1 a part of which can be attributable to genetic variants affecting known biochemical and metabolic risk factors. In the last 2 years, impressive progress has been made in understanding the genetic basis of several of these using both candidate gene and genome-wide association study (GWAS) approaches. Article see p 16 Candidate genes, coding for proteins of known biological significance in a disease process, provide a logical first step in understanding the genetics of common disease states. Populations of affected and unaffected individuals can be studied by genotyping common single-nucleotide polymorphisms (SNPs) within a gene and its regulatory sequences. Although economically attractive, this approach is acknowledged to have a number of limitations. By definition, studies are limited to genes with a known or suspected role in defining a given phenotype and do not provide new insight into biological pathways leading to disease. Furthermore, candidate gene associations often fail to replicate for multiple reasons. Sample sizes have often been inadequate to provide the statistical power required when multiple variants of small effect are tested. The original observation may have been false positive, emphasizing the need for stringent statistical thresholds. Other issues include heterogeneity of causality. For example, genetic variants affecting plasma lipid traits may have significant effects on CAD risk, but these may be less important than or interact with other risk factors including diabetes and smoking. Finally, appropriate measures must be taken to test for population stratification. Genome wide association studies (GWASs) are is an alternative approach, facilitated by the International HapMap Project and advances in genotyping technology, permitting analysis of a million or more markers across the human genome. GWASs provides an unbiased approach that has led to the identification …

Plasma 25-Hydroxyvitamin D Is Associated with Markers of the Insulin Resistant Phenotype in Nondiabetic Adults

We examined the cross-sectional association between plasma 25-hydroxyvitamin D [25(OH)D] and markers of the insulin resistant phenotype. Plasma 25(OH)D concentrations were measured in 808 nondiabetic participants of the Framingham Offspring Study. Outcome measures included fasting and 2-h post 75-g oral glucose tolerance test (OGTT) glucose and insulin; these were used to calculate the homeostatic model assessment-insulin resistance (HOMA-IR) and insulin sensitivity index (ISI(0,120)). We also measured plasma adiponectin, triacylglycerol, and HDL cholesterol concentrations as markers of the insulin-resistant phenotype. After adjusting for age, sex, BMI, waist circumference, and current smoking status, plasma 25(OH)D concentration was inversely associated with fasting plasma glucose and insulin concentrations, and HOMA-IR. Compared with the participants in the lowest tertile category of plasma 25(OH)D, those in the highest tertile category had a 1.6% lower concentration of fasting plasma glucose (P-trend = 0.007), 9.8% lower concentration of fasting plasma insulin (P-trend = 0.001), and 12.7% lower HOMA-IR score (P-trend < 0.001). After adjusting for age and sex, plasma 25(OH)D was positively associated with ISI(0,120), plasma adiponectin, and HDL cholesterol and inversely associated with plasma triacylglycerol, but these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. 25(OH)D and 2-h post-OGTT glucose were not associated. Among adults without diabetes, vitamin D status was inversely associated with surrogate fasting measures of insulin resistance. These results suggest that vitamin D status may be an important determinant for type 2 diabetes mellitus.

Co-administration of a CpG adjuvant (VaxImmuneTM, CPG 7909) with CETP vaccines increased immunogenicity in rabbits and mice

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of neutral lipids and phospholipids between lipoproteins and contributes to the regulation of the plasma concentration of high density lipoprotein cholesterol (HDL-C). Vaccines have been developed that elicit antibodies that bind to and reduce the lipid transfer function of CETP as a way to increase the plasma concentration of HDL-C and prevent or treat atherosclerosis. This study assessed the immunogenicity of two vaccine peptides. The first, CETi-1, is a dimerized synthetic peptide, including residues 461-476 of human CETP and residues 830-843 of tetanus toxoid, TT(830-843). The second, PADRE-CETP, is a monomeric peptide, in which a PADRE T cell epitope (aK-Cha-VAAWTLKAa) replaces the TT(830-843) T cell epitope of CETi-1. Both peptides were formulated with aluminum-containing adjuvants (Alhydrogel®), and tested in mice and rabbits with or without the co-administration of the investigational TLR9 agonist VaxImmuneTM (CPG 7909). In both mice and rabbits, the vaccine peptide utilizing the PADRE T cell epitope elicited stronger anti-CETP antibody responses than the CETi-1 vaccine. Also, co-administration of VaxImmune enhanced the anti-CETP antibody responses to both vaccines. Isotype analysis of the murine anti-CETP antibody response to both vaccines demonstrated a switch from IgG1 to IgG2a upon co-administration of VaxImmune. We conclude that 1) the PADRE T cell epitope is more potent than the TT(830-843) epitope in providing help for the anti-CETP antibody response; and 2) co-administration of VaxImmune with either vaccine increased immunogenicity as measured by antibody response.

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

Dietary fatty acids affect atherogenesis, which was presumed to be partly related to HDL cholesterol (HDL-C) metabolism. The major aim of the work was to analyze various ratios of n-6/n-3 PUFA diets on HDL-C metabolism in apolipoprotein E-null (apoE(-/-)) mice, which have similar symptoms to human type III familial hyperlipoproteinemia. Two-month-old male apoE(-/-) mice were fed four types of n-6/n-3 PUFA diet (group 1, 1.28; group 2, 5.03; group 3, 9.98 and group 4, 68.26) and control diet, respectively, for 6 weeks. With respect to serum apolipoprotein (apo) A-I concentration, lecithin-cholesterol acyltransferase (LCAT) activity and mRNA abundance of genes involved in HDL-C metabolism in the liver were analyzed. Group 4 diet significantly increased the plasma HDL-C and apoA-I concentrations compared with other groups. LCAT activity in serum increased with decreased ratios of n-6/n-3 PUFA. As the dietary ratio of n-6/n-3 fatty acids increased, so did mRNA levels of hepatic apoA-I, scavenger receptor B class-1 (SR-B1), LCAT, ATP binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor alpha (LXRalpha). ApoA-II mRNA level, however, had a tendency to fall. Group 4 diet increased apoA-I and ABCA1 and decreased apoA-II transcriptional levels, whereas group 1 diet decreased mRNA levels of apoA-I, LCAT, SR-B1 and ABCG1. Our data indicated that a high ratio of n-6/n-3 PUFA increased the serum HDL-C level, but did not effectively suppress atherogenesis in apoE(-/-) mice. The elevated HDL-C level is possibly due to up-regulated hepatic apoA-I and ABCA1 with suppression of apoA-Ii expression.

Diet-gene interactions between dietary fat intake and common polymorphisms in determining lipid metabolism

Current dietary guidelines for fat intake have not taken into consideration the possible genetic differences underlying the individual variability in responsiveness to dietary components. Genetic variability has been identified in humans for all the known lipid metabolim-related genes resulting in a plethora of candidate genes and genetic variants to examine in diet-gene interaction studies focused on fat consumption. Some examples of fat-gene interaction are reviewed. These include: the interaction between total intake and the 514C/T in the hepatic lipase gene promoter in determining high-density lipoprotein cholesterol (HDL-C) metabolism; the interaction between polyunsaturated fatty acids (PUFA) and the 75G/A polymorphism in the APOA1 gene plasma HDL-C concentrations; the interaction between PUFA and the L162V polymorphism in the PPARA gene in determining triglycerides and APOC3 concentrations; and the interaction between PUFA intake and the 1131TC in the APOA5 gene in determining triglyceride metabolism. Although hundreds of diet-gene interaction studies in lipid metabolism have been published, the level of evidence to make specific nutritional recommendations to the population is still low and more research in nutrigenetics has to be undertaken.

Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations

The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.

Ramadan Fasting’s Effect on Plasma Leptin, Adiponectin Concentrations, and Body Composition in Trained Young Men

To evaluate the effect of Ramadan fasting on parameters of insulin resistance in trained athletes at rest and after aerobic exercise. Nine male rugby players (age 19 +/- 2 yr, height 1.78 +/- 0.74 m) were tested 3 times: 1 week before observance of Ramadan (C), at the end of the first week (R1), and during the fourth week (R2). They performed a progressive cycle-ergometer test at each visit. Data collected at rest and at the end of aerobic exercise included simple anthropometry (body mass, body-mass index, body fat, fat-free mass), biochemical parameters (serum glucose, cholesterol, HDL cholesterol, triglycerides, creatinine, and serum proteins), and selected hormone concentrations (plasma insulin, leptin, and adiponectin). Ramadan fasting was associated with a reduction of body mass and body fat (R2 vs. C, p < .01) without significant change in leptin or adiponectin levels. Lipolysis might have occurred because of increased plasma triglycerides and HDL cholesterol concentrations.

Fasting and Postprandial Remnant-Like Particle Cholesterol Concentrations in Obese Participants Are Associated with Plasma Triglycerides, Insulin Resistance, and Body Fat Distribution

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (−2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20–25 vs. 40–45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMAIR (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R2 (adj. R2) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R2 = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMAIR, and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMAIR and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet.

A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes

Treatment of type 2 diabetes mellitus (T2DM) patients with pioglitazone results in a more favorable lipid profile, and perhaps more favorable cardiac outcomes, than treatment with rosiglitazone. Pioglitazone treatment increases VLDL-triacylglycerol clearance, but the role of de novo lipogenesis (DNL) has not been explored, and no direct comparison has been made between the thiazolidinediones (TZDs). Twelve subjects with T2DM and hypertriacylglyceridemia were randomized to either rosiglitazone or pioglitazone treatment. Stable isotope infusion studies were performed at baseline and after 20 weeks of treatment. Both treatments reduced glucose and HbA(1c) concentrations equally. Pioglitazone treatment resulted in a 40% reduction in hepatic DNL (P < 0.01) and in a 25% reduction in hepatic glucose production (P < 0.05), while rosiglitazone did not significantly change either parameter, although comparisons of changes between treatments were not significantly different. These pilot results indicate that pioglitazone reduces hepatic DNL while rosiglitazone does not. Larger follow-up studies are required to confirm differential effects of these agents definitively. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPARalpha or other non-PPARgamma actions on the liver by pioglitazone. These differences might help explain previously reported differences in lipid profiles and cardiovascular disease outcomes for rosiglitazone and pioglitazone.