Apolipoprotein (apo) E plays a key role in lipoprotein metabolism and has been proposed to modulate triglyceride (TG) lipolysis. However, no systematic investigation on lipolysis using all 3 isoforms of apoE has been performed. To clarify the role of common human apoE isoforms in the lipolysis of very low-density lipoprotein (VLDL) TGs, we overexpressed human apoE isoforms in apoE and low-density lipoprotein receptor-deficient mice using adenoviral-mediated gene transfer and used VLDL particles obtained from these mice for in vitro lipolysis assay. Overexpression of apoE, regardless of its isoforms, increased the TG content of VLDL in mice in vivo. In vitro analysis of the effect of apoE on lipolysis revealed that irrespective of its isoforms, apoE did inhibit TG lipolysis at every concentration of apoE examined, and this inhibitory effect became more pronounced as the apoE content of VLDL increased. No difference was observed in TG lipolysis activity among isoforms at low apoE/TG ratio; however, intermediate ratios of apoE/TG, which reflect physiologic VLDL apoE/TG ratios, demonstrated a significantly greater level of lipolysis inhibition in apoE2, but less so in apoE4 compared with other isoforms. This differential effect by apoE isoforms on lipolysis was attenuated at higher apoE/TG ratios; nevertheless, apoE2 still inhibited lipolysis significantly more than did apoE4. Enrichment of VLDL with apoE decreased both the apoC contents and apoC-II/C-III ratios of VLDL, contributing, at least in part, to the inhibitory function of apoE on lipolysis. The present study clarifies the differential lipolysis-modulating effect of apoE isoforms, which would help explain the difference in pre- and postprandial TG levels among humans carrying different apoE isoforms.

Apolipoprotein C-I (apoCI) is implicated in lipid metabolism and inflammatory response, both important risk factors for human heart disease. However, most findings come from in vitro or animal studies, whereas data on human apoCI are sparse. To elucidate the role of apoCI in human disease, we analyzed a functional polymorphism in the promoter region of the apoCI gene in relation to blood lipids, C-reactive protein (CRP), coronary artery disease (CAD), and myocardial infarction (MI). Rs11568822 is a 4-base pair insertion/deletion (Ins/Del) polymorphism, and the Ins allele leads to a higher transcription in vitro compared with the Del allele. This polymorphism was analyzed in the Intergene study, a case-control study for CAD (N = 1236), and the Stockholm Heart Epidemiology Program, a case-control study for MI (N = 2774). Subjects homozygous for the Ins genotype had significantly higher serum levels of triglycerides (P = .01 and P = .006) and lower serum levels of CRP (P = .02 and P < .0001) compared with all other subjects in both studies. Similar results were obtained when analyzing only the controls of both studies (P = .002 and P = .0002, triglycerides; P = .002 and P < .0001, CRP). However, apoCI was not associated with CAD or MI. In conclusion, our data show that apoCI genotype is associated with serum levels of triglycerides and CRP, confirming the role of apoCI in lipid metabolism and suggesting that it also influences inflammation.

Nonnutritive sweeteners (NNSs) have been studied in terms of their potential roles in type 2 diabetes, obesity, and related metabolic disorders. Several studies have suggested that NNSs have several specific effects on metabolism such as reduced postprandial hyperglycemia and insulin resistance. However, the detailed effects of NNSs on body adiposity and energy metabolism have not been fully elucidated. We investigated the effects of an NNS on energy metabolism in mice with diet-induced obesity (DIO).

A variety of calorie restriction diets and fasting regimens are popular among overweight people. However, starvation could result in unexpected cardiovascular effects. Therefore, it is necessary to evaluate the short-term effects of diets on cardiovascular function, energy metabolism and potential risk of heart damage in case of myocardial infarction. The objective of the present study was to investigate whether the increased level of glucose oxidation or reduction of fatty acid (FA) load in the fed state provides the basis for protection against myocardial infarction in an experimental rat model of ischemia-reperfusion.

Excessive adipose glucocorticoid action is associated with insulin resistance, but the mechanisms linking adipose glucocorticoid action to insulin resistance are still debated. We hypothesized that insulin resistance from excess glucocorticoid action may be attributed in part to increased ectopic lipid deposition in liver.

Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF-β family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance.

Polymorphisms in the APOC3 and APOA5 genes, from the APOA1/APOC3/APOA4/APOA5 gene cluster on chromosome 11q23, have been associated with interindividual variation in plasma triglycerides. APOA5 polymorphisms implicated include 2 in the promoter region (-1131 T/C and -3 A/G) and 1 in exon 2 (+56 C/G). APOC3 polymorphisms implicated include 1 (SstI) in the 3' untranslated region and 1 (-2854 G/T) in the APOC3-APOA4 intergenic region. We analyzed the associations of haplotypes and multilocus genotypes of these polymorphisms on longitudinal serum triglyceride profiles in 360 African American and 823 white subjects from the Bogalusa Heart Study. Subjects were examined from 2 to 8 times (mean +/- SD, 5.4 +/- 1.3) between 1973 and 1996, at ages ranging from 4 to 38 years, with 1978 observations in African Americans and 4465 in whites. Serum triglycerides were significantly higher among whites across all ages. Allele frequencies differed significantly between African Americans and whites at all but the APOA5 +56 C/G locus. Linkage disequilibrium among the loci was higher in whites and haplotype diversity lower: 6 haplotypes had estimated frequencies of more than 1% in African Americans, 5 in whites. Individually, all polymorphisms except APOC3 -2854 G/T showed significant associations with triglyceride levels in the full sample. However, genotype models including all 5 loci showed significant triglyceride associations for only 3 (APOC3 SstI, APOA5 -1131 T/C, and APOA5 +56 C/G); significant interactions among them indicated their effects were not independent. Neither APOC3 -2854 G/T nor APOA5 -3 A/G had significant effects when the other 3 loci were in the models. The EM algorithm was used to estimate haplotype frequencies and assign haplotype probabilities to individuals, which is conditional on their genotypes; individuals' haplotype probability vectors were then used as predictors in multilevel mixed models of longitudinal triglyceride profiles. Of haplotypes comprising, in order, APOC3 SstI and -2854 G/T and APOA5 -1131 T/C, -3 A/G, and +56 C/G, 3 were significantly associated with higher triglycerides, even after adjusting for multiple tests: GGTAG (P = .002), GTTAG (P < .0001), and CGCGC (P = .0002). Each GGTAG haplotype carried would be expected to raise triglyceride levels (relative to those of GTTAC homozygotes) by approximately 19 mg/dL, each GTTAG haplotype by approximately 15 mg/dL, and each CGCGC haplotype by approximately 7 mg/dL. Haplotypes comprising the 3 loci implicated by genotype analyses (SstI, -1131 T/C, and +56 C/G) were also tested: haplotypes C_C_C and G_T_G significantly raised triglycerides, even after adjustment for multiple comparisons (P < .002 for both), with each copy of C_C_C expected to raise triglycerides by approximately 7 mg/dL and each copy of G_T_G by approximately 15 mg/dL. Overall, our findings support those of others in associating specific polymorphisms and haplotypes in the APOA1/C3/A4/A5 gene cluster with higher serum triglyceride levels. However, the degree to which polymorphisms in the APOC3 and APOA5 genes may be independently associated with triglyceride levels remains to be determined.

The pro-inflammatory state and elevated plasma levels of post-prandial triglycerides (TG) are associated with increased cardiovascular disease risk. Recent studies suggested that the increase in the production rate of post-prandial lipoproteins observed in patients with insulin resistance (IR) may be caused, at least in part, by the dysregulation of intestinal insulin sensitivity triggered by inflammation.

The purpose of this study was to compare the effects of 3 different modalities of exercise on metabolic control, insulin resistance, inflammatory markers, adipocytokines, and tissue expression of insulin receptor substrate (IRS)-1 after 12 weeks of training among patients with type 2 diabetes mellitus. Forty-eight patients with type 2 diabetes mellitus were randomly assigned to 4 groups of training (3 times a week, 60 minutes per session): aerobic group (n = 12), resistance group (n = 12), combined (aerobic and resistance) group (n = 12), and control group (n = 12). Fasting and postprandial blood glucose, glycated hemoglobin, lipid profile, insulin resistance index (homeostasis model assessment of insulin resistance), adipocytokines (adiponectin, visfatin, and resistin), tumor necrosis factor, interleukin, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline and at the end of the study. Patients also underwent a muscle microbiopsy before and after training to quantify IRS-1 expression. All 4 groups displayed decreases in blood pressure, fasting plasma glucose, postprandial plasma glucose, lipid profile, and hs-CRP (P < .05); and there was no difference across the groups. After training, the IRS-1 expression increased by 65% in the resistance group (P < .05) and by 90% in the combined group (P < .01). Exercise training favorably affects glycemic parameters, lipid profile, blood pressure, and hs-CRP. In addition, resistance and combined training can increase IRS-1 expression.

PTEN haploinsufficiency plays an important role in prostate cancer development in men. However, monoallelic deletion of Pten gene failed to induce high prostate intraepithelial neoplasia (PIN) until Pten+/- mice aged or fed a high-calorie diet. Because CEACAM1, a cell adhesion molecule with a potential tumor suppression activity, is induced in Pten+/- prostates, the study aimed at examining whether the rise of CEACAM1 limited neoplastic progression in Pten+/- prostates.

Adiponectin, a protein secreted by adipose tissue, has antiatherogenic, anti-inflammatory, and insulin-sensitizing actions. We examined the relationship between plasma adiponectin and adiposity, insulin resistance, plasma lipids, glucose, leptin, and anthropometric measurements in 316 adult men and 353 adult women Yup'ik Eskimos in Southwest Alaska. Adiponectin concentration was negatively associated with body mass index, percentage of body fat, sum of skin folds, waist circumference, triglycerides, insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]), fasting insulin, and leptin in both men and women, and also with glucose in women. Adiponectin concentration correlated positively with high-density lipoprotein cholesterol concentration, and also with low-density lipoprotein cholesterol in women. Insulin-sensitive individuals (HOMA-IR <3.52, n = 442) had higher plasma adiponectin concentrations than more insulin-resistant individuals (HOMA-IR >or=3.52, n = 224): 11.02 +/- 0.27 microg/mL vs 8.26 +/- 0.32 microg/mL, P < .001. Adiponectin concentrations did not differ between groups of participants with low and high level of risk for developing coronary heart disease. No difference in plasma adiponectin levels was found among Yup'ik Eskimos and whites matched for sex, age, and body mass index. In conclusion, circulating adiponectin concentrations were most strongly associated with sum of skin folds in Yup'ik men and with high-density lipoprotein cholesterol levels, sum of skin folds, waist circumference, and insulin and triglycerides concentrations in Yup'ik women.

Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects.

Decrease in adiponectin level, a common feature in patients with type 2 diabetes mellitus, is considered to predict cardiovascular events. Elevated oxidized low-density lipoprotein (oxLDL), formed within the arterial wall, is commonly seen as part of the atherogenic profile. We investigated the association of adiponectin and oxLDL in 58 patients with type 2 diabetes mellitus and ischemic coronary artery disease. In addition to adiponectin, the serum lipid profile (including oxLDL), plasminogen activator inhibitor 1, high-sensitivity C-reactive protein, and whole-body glucose uptake determined by euglycemic-hyperinsulinemic clamp were evaluated. The average adiponectin level was 7.1 +/- 3.5 microg/mL and was higher in female than in male patients (P = .011). Adiponectin level correlated with whole-body glucose uptake (P = .037) and high-density lipoprotein (HDL) cholesterol concentration (P = .007) and was inversely associated with oxLDL (P = .005), triglycerides (P = .010), and plasminogen activator inhibitor 1 (P = .004). No association was found between adiponectin and high-sensitivity C-reactive protein or LDL cholesterol levels. In multiple linear regression analysis, adiponectin contributed to oxLDL concentration, whereas total cholesterol, LDL and HDL cholesterol, and triglycerides did not. In conclusion, our results suggest that low adiponectin concentration indicates increased oxidative state in the arterial wall, which further supports previous data on the role of adipose tissue in atherogenesis.

Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects.

Free fatty acids (FFAs) lead to the activation of inflammatory pathways related to the induction of insulin resistance. Visfatin is known to play a role in obesity-related metabolic diseases and inflammatory conditions. Here, the role of visfatin in FFA-induced inflammation was investigated in hepatocytes. The following factors were examined: (1) the protein and messenger RNA (mRNA) expression of visfatin in the liver tissue of insulin-resistant rats and in (2) in HepG2 cells treated with palmitate, (3) the palmitate-induced mRNA expression and protein synthesis of interleukin-6 and tumor necrosis factor-α in HepG2 cells transfected with visfatin-specific small interfering RNA, and (4) the expression of visfatin in HepG2 cells treated with a nuclear factor-κB (NF-κB) inhibitor (SN50) and infected with Ad-IκBα. The protein and mRNA levels of visfatin were significantly higher in insulin-resistant rat liver tissue compared with the control group. Visfatin expression and protein synthesis significantly increased in HepG2 cells treated with palmitate in a time- and concentration-dependent manner. Visfatin-specific small interfering RNA significantly decreased the palmitate-induced mRNA expression and protein synthesis of interleukin-6 and tumor necrosis factor-α. A NF-κB inhibitor induced the downregulation of visfatin in HepG2 cells following treatment with palmitate. HepG2 cells infected with Ad-IκBα showed decreased expression of visfatin following treatment with palmitate. The expression of visfatin is closely associated with the expression of proinflammatory cytokines in FFA-induced inflammation and is significantly decreased by NF-κB inhibition in HepG2 cells. Visfatin may play a role in FFA-induced inflammation in hepatocytes through the NF-κB pathway.

The purposes of this study were (1) to determine the association between lipoprotein subfraction profiles and metabolically healthy overweight (MHO) phenotype, as defined by visceral adiposity; and (2) to identify the strongest predictor of metabolic health among the lipoprotein measurements.

Serum uric acid levels are associated with hypertension, cardiovascular disease, and renal disease. Uric acid has been shown to be heritable; however, genome-wide linkage analyses have not been reported. Genome-wide multipoint variance components linkage analyses with 401 markers spaced at approximately 10 centimorgan (cM) were conducted on 1258 subjects of the Framingham Heart Study, using the average of two serum uric acid measurements obtained in examinations 1 and 2 around 1971 and 1979. Covariates in fully adjusted model included sex, age, body mass index (BMI), serum creatinine, alcohol consumption, diabetes, diuretic treatment, and triglycerides. To investigate possible pleiotropic effects between uric acid and covariates that may have a genetic component, bivariate linkage analyses of uric acid with BMI, triglycerides, and glucose were conducted at the uric acid linkage regions. The heritability of uric acid was 0.63. The highest multipoint log-of-the-odds (LOD) score was 3.3 at 50 cM on chromosome 15 for age-sex-adjusted uric acid, but decreased to 1.5 after multivariable adjustment. Additional evidence of linkage was seen on chromosomes 2 (LOD score 1.1 at 4 cM) and 8 (LOD score 1.7 at 6 cM) for multivariable-adjusted uric acid. Pleiotropic effects were only found between uric acid and glucose and BMI at chromosomes 8 and 15 linkage locations, respectively. We have identified several novel loci linked to uric acid. We found possible pleiotropic effects between uric acid and BMI and glucose. Further research is necessary to identify the genes involved in uric acid metabolism and their roles in hypertension, cardiovascular disease, and renal disease.

Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms.

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (< or = 28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (> or = 73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the epsilon2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.

Recent studies have found that baseline inflammatory status affected the response of the lipid profile to diet intervention. The goal of this study was to determine whether baseline inflammatory status, as reflected in C-reactive protein, interleukin 6, and tumor necrosis factor alpha, affected the lipid and insulin response to a weight loss intervention. A second goal was to determine whether inflammatory markers were related to traditional metabolic risk factors, such as lipids and insulin, in our sample of 190 overweight (body mass index, 27-30 kg/m2) premenopausal women. Body composition, fat distribution, serum lipids, insulin sensitivity (Si), and markers of inflammation were assessed at baseline and after weight loss to body mass index<25 kg/m2. All measurements were taken after a 4-week period of weight maintenance. Mixed-model, repeated-measures analysis was used to determine whether the interaction of baseline inflammatory status and time was significant in determining the changes in metabolic risk factors (Si and lipids) with weight loss. Weight loss was associated with significant reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and insulin, and increases in high-density lipoprotein cholesterol and Si. Triglycerides were higher (P=.054) and Si lower (P=.057) with increasing C-reactive protein tertile. The interaction of baseline inflammatory status and time was not significant for any outcome variable of interest. These results do not support the hypothesis that baseline inflammatory status affects the lipid and insulin response to a weight loss intervention. However, in these young, healthy women, weight loss had a beneficial impact on both inflammatory status and risk factors for chronic metabolic disease.