Large VLDL Research Articles

Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia

Objective Determine the effects of treatment with a selective PPAR-δ agonist ± statin on plasma lipoprotein subfractions in dyslipidemic individuals. Methods Ion mobility analysis was used to measure plasma concentrations of subfractions of the full spectrum of lipoprotein particles in 166 overweight or obese dyslipidemic individuals treated with the PPAR-δ agonist MBX-8025 (50 and 100 mg/d) ± atorvastatin (20 mg/d) in an 8-week randomized parallel arm double blind placebo controlled trial. Results MBX-8025 at both doses resulted in reductions of small plus very small LDL particles and increased levels of large LDL, with a concomitant reduction in large VLDL, and an increase in LDL peak diameter. This translated to reversal of the small dense LDL phenotype (LDL pattern B) in ∼90% of the participants. Modest increases in HDL particles were confined to the smaller HDL fractions. Atorvastatin monotherapy resulted in reductions in particles across the VLDL–IDL–LDL spectrum, with a significantly smaller reduction in small and very small LDL vs. MBX-8025 100 mg/d (−24.5 ± 5.3% vs. −47.8 ± 4.9%), and, in combination with MBX-8025, a reversal of the increase in large LDL. Conclusion PPAR-δ and statin therapies have complementary effects in improving lipoprotein subfractions associated with atherogenic dyslipidemia.

High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study

BackgroundPostprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.ResultsPostprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.ConclusionsWe have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.

The Effect of Alcohol on Postprandial and Fasting Triglycerides

Alcohol has a significant additive effect on the postprandial triglyceride peak when it accompanies a meal containing fat, especially saturated fat. This results from a decrease in the breakdown of chylomicrons and VLDL remnants due to an acute inhibitory effect of alcohol on lipoprotein lipase activity. Furthermore, alcohol increases the synthesis of large VLDL particles in the liver, which is the main source of triglycerides in the hypertriglyceridemia associated with chronic excessive alcohol intake. In case of chronic consumption, lipoprotein lipase activity seems to adapt itself. The effect of alcohol on adipose tissues is less clear. Sometimes, a severe hypertriglyceridemia induced by alcohol (SHIBA) can be observed, especially in patients with type 2 diabetes mellitus and/or obesity increasing the risk of pancreatitis.

P44 Use of Intralipid infusion to analyse apolipoprotein B (apoB) and HCV RNA kinetics in chronic infection

IntroductionProduction of infectious HCV is dependent on hepatocytes VLDL assembly, maturation, and secretory machinery. ApoB-100 is the structural apolipoprotein of large VLDL (VLDL1), small VLDL2, and LDL. Although HCV production...

The association of hs-CRP with fasting and postprandial plasma lipids in patients with type 2 diabetes is disrupted by dietary monounsaturated fatty acids

The aim of the study was to evaluate whether two dietary approaches recommended for diabetes mellitus and cardiovascular prevention-high-MUFA or complex carbohydrates/fiber-differently influence inflammation. A 4-week crossover study in 12 individuals with type 2 diabetes was performed. Fasting and postprandial hs-CRP plasma levels were not significantly different after a high-carbohydrate/high-fiber/low-glycemic index (CHO/fiber) and a high-MUFA diet. Compared with fasting, hs-CRP levels decreased significantly after the MUFA but not after the CHO/fiber meal. Triglyceride-rich lipoproteins were significantly lower after the CHO/fiber than the MUFA diet. At fasting and postprandially, hs-CRP correlated with triglyceride in whole plasma, chylomicrons, small and large VLDL after the CHO/fiber but not after the MUFA diet. In conclusion, a MUFA-rich diet and a carbohydrate/fiber-rich diet induced similar effects on plasma hs-CRP concentrations. However, these dietary approaches seem to influence hs-CRP levels through different mechanisms. i.e., direct acute postprandial effects by MUFA and triglyceride-rich lipoproteins mediated effects by CHO/fiber.

Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study)

Diabetic kidney disease, diagnosed by urinary albumin excretion rate (AER), is a critical symptom of chronic vascular injury in diabetes, and is associated with dyslipidemia and increased mortality. We investigated serum lipids in 326 subjects with type 1 diabetes: 56% of patients had normal AER, 17% had microalbuminuria (20 ≤ AER < 200 μg/min or 30 ≤ AER < 300 mg/24 h) and 26% had overt kidney disease (macroalbuminuria AER ≥ 200 μg/min or AER ≥ 300 mg/24 h). Lipoprotein subclass lipids and low-molecular-weight metabolites were quantified from native serum, and individual lipid species from the lipid extract of the native sample, using a proton NMR metabonomics platform. Sphingomyelin (odds ratio 2.53, P < 10−7), large VLDL cholesterol (odds ratio 2.36, P < 10−10), total triglycerides (odds ratio 1.88, P < 10−6), omega-9 and saturated fatty acids (odds ratio 1.82, P < 10−5), glucose disposal rate (odds ratio 0.44, P < 10−9), large HDL cholesterol (odds ratio 0.39, P < 10−9) and glomerular filtration rate (odds ratio 0.19, P < 10−10) were associated with kidney disease. No associations were found for polyunsaturated fatty acids or phospholipids. Sphingomyelin was a significant regressor of urinary albumin (P < 0.0001) in multivariate analysis with kidney function, glycemic control, body mass, blood pressure, triglycerides and HDL cholesterol. Kidney injury, sphingolipids and excess fatty acids have been linked in animal models—our exploratory approach provides independent support for this relationship in human patients with diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-011-0343-y) contains supplementary material, which is available to authorized users.

Lipoprotein Subclass Abnormalities and Incident Hypertension in Initially Healthy Women

Abnormalities in traditional lipids, particularly decreased HDL cholesterol and increased triglycerides, can precede the onset of hypertension. Whether lipoprotein particle size or subclass concentrations play a role in the development of hypertension is unknown. We followed 17 527 initially healthy women without baseline hypertension prospectively for 8 years. At baseline, information regarding traditional lipids and hypertension risk factors was obtained, and lipoprotein size and subclass concentrations were measured by nuclear magnetic resonance spectroscopy. Baseline lipoprotein size and subclass concentrations were significantly associated with incident hypertension. Although LDL cholesterol was not associated with hypertension [odds ratio (OR) for quintile 5 vs 1: 1.08 (95% CI 0.96-1.20)], increased concentrations of LDL particles were associated with greater risk [OR 1.73 (1.54-1.95)], especially small LDL particles [OR 1.62 (1.45-1.83)]. Increased HDL cholesterol was associated with lower risk of hypertension [OR for quintile 5 vs 1: 0.79 (0.70-0.89)]. By contrast, increased concentrations of HDL particles had greater risk [OR 1.48 (1.32-1.67)], especially small HDL particles [OR 1.36 (1.22-1.53)], whereas large HDL particles had lower risk [OR 0.80 (0.71-0.90)]. Triglycerides and triglyceride-rich VLDL particles were positively associated with hypertension, with large VLDL particles associated with greater risk [OR 1.68 (1.50-1.89)]. Adding particle subclasses improved discrimination over a model with traditional lipids and risk factors (c-statistic 0.671 compared to 0.676; P < 0.001). In this study of initially healthy women, lipoprotein particle size and subclass concentrations were associated with incident hypertension and provided additive information to traditional lipids and risk factors.

A clustering analysis of lipoprotein diameters in the metabolic syndrome

BackgroundThe presence of smaller low-density lipoproteins (LDL) has been associated with atherosclerosis risk, and the insulin resistance (IR) underlying the metabolic syndrome (MetS). In addition, some research has supported the association of very low-, low- and high-density lipoprotein (VLDL HDL) particle diameters with components of the metabolic syndrome (MetS), although this has been the focus of less research. We aimed to explore the relationship of VLDL, LDL and HDL diameters to MetS and its features, and by clustering individuals by their diameters of VLDL, LDL and HDL particles, to capture information across all three fractions of lipoprotein into a unified phenotype.MethodsWe used nuclear magnetic resonance spectroscopy measurements on fasting plasma samples from a general population sample of 1,036 adults (mean ± SD, 48.8 ± 16.2 y of age). Using latent class analysis, the sample was grouped by the diameter of their fasting lipoproteins, and mixed effects models tested whether the distribution of MetS components varied across the groups.ResultsEight discrete groups were identified. Two groups (N = 251) were enriched with individuals meeting criteria for the MetS, and were characterized by the smallest LDL/HDL diameters. One of those two groups, one was additionally distinguished by large VLDL, and had significantly higher blood pressure, fasting glucose, triglycerides, and waist circumference (WC; P < .001). However, large VLDL, in the absence of small LDL and HDL particles, did not associate with MetS features. These associations held after additionally controlling for VLDL, LDL and HDL particle concentrations.ConclusionsWhile small LDL diameters remain associated with IR and the MetS, the occurrence of these in conjunction with a shift to overall larger VLDL diameter may identify those with the highest fasting glucose, TG and WC within the MetS. If replicated, the association of this phenotype with more severe IR-features indicated that it may contribute to identifying of those most at risk for incident type II diabetes and cardiometabolic disease.

Lipoprotein Lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS

BackgroundPrevious analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328).FindingsMixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04).ConclusionsThis was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.

Does non-alcoholic fatty liver impair alterations of plasma lipoproteins and associated factors in metabolic syndrome?

Background Hepatic steatosis (HS) is closely associated to metabolic syndrome (MS). Both, VLDL-triglyceride oversecretion and intrahepatic deposits, can take place. We evaluated VLDL characteristics, CETP, hepatic lipase (HL), IDL and small dense LDL (sdLDL), in patients with HS associated to MS. Methods We studied 3 groups matched by age and sex: 25 MS patients with HS (diagnosed by ultrasonography), 25 MS patients without HS and 25 healthy controls. Main measurements were: lipid profile, free fatty acids, VLDL composition, VLDL size by HPLC, CETP and HL activities, IDL-cholesterol and sdLDL-cholesterol. Results Patients with HS presented higher triglyceride levels, HOMA-IR and free fatty acids, VLDL mass and VLDL-apoB (p < 0.05). No differences in VLDL composition were observed. MS groups presented higher proportion of large VLDL than controls (p < 0.05). HS group showed higher CETP than controls (p = 0.01) and almost higher than MS without HS (p = 0.06). CETP correlated with VLDL-cholesterol content, r = 0.48, p < 0.005. The increase in sdLDL-cholesterol correlated with CETP (r = 0.47) and HL (r = 0.56), independent of insulin resistance (p < 0.003). Conclusion Despite intrahepatic fat, patients with HS secreted higher number of VLDL particles. CETP would have a remodeling action on VLDL in circulation, enriching it in cholesterol and also favoring, together with HL, the formation of sdLDL.

Differences in lipoprotein particle subclass distribution for Japanese Americans in Hawaii and Japanese in Japan: The INTERLIPID Study

Current data suggest that low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass concentrations relate directly to the risk of coronary heart disease (CHD). Earlier Studies indicated that Japanese in Japan had lower rates of CHD than Japanese Americans in Hawaii. Rates of CHD appear to continue to be lower in Japan despite increasing cholesterol levels in Japan and decreasing CHD rates in the United States. To provide insight into CHD rate differences. Nuclear Magnetic Resonance (NMR) measurements of lipoprotein subclasses were used to assess lipoprotein particle concentration and size in samples from these two genetically similar populations in Japan and Hawaii. Japanese Americans had significantly higher age- and risk factor- adjusted concentrations of lipoprotein particles implicated in atherogenesis, including large very low density lipoprotein (VLDL; P < 0.001), small LDL (P < 0.001), and small HDL (women, P < 0.001; men, P < 0.01), and significantly lower concentrations of large LDL (P < 0.001) and the putative cardio-protective large HDL (P < 0.05) than Japanese in Japan. Average age- and risk factor- adjusted LDL and HDL particle sizes were also significantly (P < 0.001) smaller in Japanese Americans. Adjustment for body mass index markedly reduced the differences in some lipoprotein measures, including total LDL and large HDL particle concentrations for both genders, total VLDL particle concentration for women, and large VLDL concentration and average HDL particle size for men. Differences in lipoprotein subclass distributions and lifestyle factors such as body weight may contribute to differences in CHD incidence for Japanese in Japan and Japanese Americans.

Heterogeneous Postprandial Lipoprotein Responses in the Metabolic Syndrome, and Response to Fenofibrate Therapy

Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5h) versus late (8h) postprandial triglyceride responses. Fifty-five subjects with fasting hypertriglyceridemia (≥1.7mmol/L (150mg/ dL) and <5.8mmol/L (500mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160mg/d) or placebo for 12weeks in a double-blind controlled clinical trial. A standardized fat load (50g/m(2)) was given orally after a 12h fast. Blood specimens were obtained at 0h (fasting), 3.5h, and 8h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate.

NMR-determined lipoprotein subclass profile is associated with dietary composition and body size

Background and aims Dyslipidemia is influenced by diet and body habitus. The Nuclear Magnetic Resonance spectroscopy lipoprotein subclass profile (NMR-LSP) is associated with diabetes and its vascular complications; and an NMR-LSP featuring large VLDL particles and small LDL and HDL particles is linked with cardiovascular disease (CVD). Thus interventions which favourably modify NMR-LSP may reduce risk for diabetes, its complications and CVD. The study aim was to investigate the associations between NMR-LSP, dietary composition and body size measures using data from the Melbourne Collaborative Cohort Study (MCCS). Methods and results NMR-LSP was assessed in 313 men and 403 women (median age 54 years) randomly selected from a community-based cohort study. Diet was assessed using a specifically developed food frequency questionnaire (FFQ), and body size was assessed by body mass index (BMI) or waist:hips ratio (WHR). To simplify the 15 NMR-LSP variables, factor analysis was used to derive a single factor. Multivariate linear regression with this factor score as the dependent variable demonstrated that in men, total PUFA and n-6 dietary fat intake and BMI were associated with a more atherogenic NMR-LSP pattern; while in women dietary glycemic index and WHR demonstrated positive associations, and n-3 fat intake an inverse association. Conclusions We developed a single factor score to summarize the NMR-LSP that has the benefit of combining all aspects of the NMR-LSP and accounting for correlations between them. We have shown correlations between the NMR-LSP and body size and dietary composition.

Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet

Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) [Lp(a)], a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles.

Ethnic differences in lipoprotein subclasses in obese adolescents: importance of liver and intraabdominal fat accretion

Recently, the deleterious metabolic effects of visceral fat [visceral adipose tissue (VAT)] deposition were challenged, and liver fat emerged as having a key independent role in the modulation of cardiometabolic risk factors. We explored the relation between liver fat content and VAT in 3 ethnic groups and evaluated whether the ethnic differences in the distributions of lipoprotein concentrations and sizes were associated with the hepatic fat fraction (HFF), VAT, or both. In a multiethnic group of 33 white, 33 African American, and 33 Hispanic obese adolescents with normal glucose tolerance, we measured VAT and HFF by using magnetic resonance imaging. Fasting lipoprotein particle number and size were measured by using nuclear magnetic resonance spectroscopy. To assess the association between VAT and HFF, we categorized VAT into tertiles. In each ethnic group, HFF values increased between successive tertiles of VAT. After multivariate adjustment and in comparison with the 2 other groups, African Americans showed lower triglyceride (P = 0.001) and higher HDL (P = 0.03) concentrations, lower concentrations of total (P = 0.007), large (P = 0.005), and medium (P lt 0.0001) VLDL, but higher concentrations of large HDL particles (P = 0.01) and larger HDL (P = 0.005). In multivariate linear models, independent of ethnicity, VAT was a significant predictor for large HDL (P = 0.003) and total small LDL (P = 0.001) concentrations, whereas HFF significantly predicted large VLDL (P = 0.03) concentrations. Liver fat accretion, independent of VAT, may play a role in the ethnic differences seen in large VLDL particles. This trial was registered at clinicaltrials.gov as NCT00536250.

Serum n−6 fatty acids and lipoprotein subclasses in middle-aged men: the population-based cross-sectional ERA-JUMP Study

The associations of serum omega-6 (n-6) fatty acids with lipoprotein subclasses at the population level are uncertain. We aimed to examine associations between major n-6 fatty acids [ie, linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6)] and the lipoprotein subclasses VLDL, LDL, and HDL. We conducted a cross-sectional study in 1098 participants using population-based data from US white, Japanese American, Japanese, and Korean men aged 40-49 y. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Multiple linear regression models as a function of each fatty acid were used after adjustment for age, population, body mass index, pack-years of smoking, alcohol consumption, diabetes, hypertension, and omega-3 (n-3) and trans fatty acids. Serum LA was inversely associated with large VLDL (beta = -0.62, P < 0.001), total LDL (beta = -22.08, P < 0.001), and small LDL (beta = -31.89, P < 0.001) particle concentrations and VLDL size (beta = -0.72, P < 0.001). Serum LA was positively associated with large HDL particle concentration (beta = 0.21, P < 0.001) and HDL size (beta = 0.03, P < 0.001). The patterns of association of AA with large VLDL and large HDL particle concentrations were comparable with those of LA. At the population level, higher serum concentrations of LA were significantly associated with lower concentrations of total LDL particles. Higher serum concentrations of LA and AA were significantly associated with a lower concentration of large VLDL particles and a higher concentration of large HDL particles. These associations were consistent across the population groups. This trial was registered at clinicaltrials.gov as NCT00069797.

Reductions of atherogenic lipoproteins are related to concentrations of plasma carotenoids in women following a Mediterranean‐style low glycemic diet

We investigated the effects of a Mediterranean‐style low glycemic diet with (n=20) or without (n=15) a medical food containing soy protein and plant sterols, rho iso‐alpha acids, and proanthocyanidins on plasma carotenoid concentrations and on lipoprotein subfractions and size in 35 women classified with metabolic syndrome. Independent of treatment, women had an increase in plasma lutein (P &lt;0.0001), zeaxanthin (P &lt; 0.05) and beta‐carotene (P &lt; 0.0001), while lycopene was reduced (P &lt; 0.05) after 12 wk. LDL cholesterol (LDL‐C) was reduced from 139.5 ± 34.6 to 113.4 ± 33.7 mg/dL (P &lt; 0.0001). In addition, decreases were observed in the atherogenic subfractions: large VLDL (P &lt; 0.05), small LDL (P &lt; 0.00001) and medium HDL (p &lt; 0.05). Plasma lutein concentrations at wk 12 were negatively correlated with large VLDL (r= −0.349, P &lt; 0.05) and small LDL (r= −0.340, P &lt; 0.05) and positively correlated with LDL size (r = 0.337, P &lt; 0.05). In contrast, plasma lycopene was positively correlated with LDL‐C. The data indicate that women complied with the dietary regimen by increasing vegetable intake. The decrease in high glycemic foods rich in lycopene such as pasta and pizza may be responsible for the lowering of this carotenoid in plasma after 12 wk. The results also suggest that lutein transport in plasma is associated with the formation of larger LDL while the lowering in plasma LDL‐C is associated with the lowering of plasma lycopene. [Supported by MetaProteomics LLC, Gig Harbor, WA]

A Mediterranean‐style low glycemic load diet decreases the risk for heart disease by decreasing atherogenic lipoproteins. Addition of a medical food containing plant sterols and soy protein has a more favorable effect on LDL metabolism

We assessed lipoprotein profiles of women classified with metabolic syndrome (MetS) and with elevated plasma LDL cholesterol (LDL‐C) adhering to a Mediterranean low glycemic diet alone (n = 40) or accompanied by intake of a medical food containing plant sterols, soy protein, rho iso‐alpha acids, and proanthocyanidins (PSS) (n = 44). Decreases in energy intake from baseline (p &lt; 0.00001) paralleled with a decrease in carbohydrate and an increase in protein (p &lt; 0.05). Both groups experienced favorable impacts on MetS parameters, with decreases in waist circumference, plasma triglycerides (TG), and blood pressure (p &lt; 0.01). In addition, decreases in trunk fat were observed (p&lt; 0.0001) for all subjects. While LDL‐C and apolipoprotein (apo) B decreased in all subjects (p &lt; 0.01), there was a greater decrease in the PSS group (p &lt; 0.01). All subjects had a decrease in atherogenic large VLDL (p &lt; 0.0005) and small LDL particles (p &lt; 0.0001). In agreement with decreases in medium HDL (p &lt; 0.001), apo A‐II, associated with atherogenicity, decreased as well (p &lt; 0.001). Lastly, decreases were noted in levels of apo C‐III and E (p &lt; 0.01), which are implicated in hypertriglyceridemia. The data suggest that the dietary prescription improved TG metabolism by decreasing the formation of large VLDL and by reducing apolipoproteins interfering with lipoprotein lipase activity. Inclusion of PSS imparted further beneficial effects associated with LDL metabolism. [Supported by MetaProteomics, LLC, Gig Harbor, WA]

Abnormalities in lipoprotein kinetics in Type 2 diabetes

Lipoprotein kinetic abnormalities in patients with Type 2 diabetes, are the basis of diabetic dyslipidemia, which is likely to play an important role in the development of atherogenesis. In Type 2 diabetes, all lipoproteins (VLDL, IDL, LDL and HDL) demonstrate significant kinetic abnormalities. Hypertriglyceridemia is due mainly to increased production of VLDL (mostly large VLDL1 particles, potentially atherogenic) and, to a lesser extent, to reduced catabolism of VLDL and IDL. Low HDL-C is the result of increased catabolism of HDL. Although plasma LDL-C level is usually normal in patients with Type 2 diabetes, LDL turnover is significantly reduced and, as a consequence, LDL plasma residence time is increased, which is potentially harmful. The pathophysiology of lipid kinetic abnormalities in Type 2 diabetes has not yet been completely explained. However, insulin resistance and the ‘relative’ insulin deficiency observed in patients with Type 2 diabetes, are likely to play a key role in lipid kinetic abnor...

A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats

We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (approximately 70%); detoxification, steroid, and sulfur metabolism (approximately 65%) as well as cell growth/proliferation and protein synthesis/transformation (approximately 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor alpha significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease.