Sudeep Shrestha

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

BackgroundMicrosomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver.MethodsMale guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism.ResultsPlasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment.ConclusionThese results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

Dietary Green Tea Extract Lowers Plasma and Hepatic Triglycerides and Decreases the Expression of Sterol Regulatory Element-Binding Protein-1c mRNA and Its Responsive Genes in Fructose-Fed, Ovariectomized Rats

The objective of this study was to determine whether green tea (GT) inhibits the expression of genes regulating hepatic lipogenesis and intestinal lipid transport in fructose-fed ovariectomized (OX) rats. OX rats were assigned to: 1) a control group (S) fed the AIN-93G diet with corn starch as the major carbohydrate source; 2) another control group (F) fed the same diet but containing fructose at 60% as the major carbohydrate source; 3) a group fed the F diet but containing 0.5% GT; and 4) a group fed the F diet containing 1% GT. At 6 wk, plasma and liver triglyceride (TG) and cholesterol and expression of liver sterol regulatory element-binding protein-1c (SREBP-1c) and selected genes involved in lipogenesis and lipid transport were measured. Fructose elevated plasma TG and cholesterol compared with the S group. GT at 0.5 and 1.0% markedly lowered plasma and liver TG. Fructose increased the expression of SREBP-1c, fatty acid synthase, and stearoyl-CoA desaturase 1 mRNA in the liver, whereas GT decreased the expression of these lipogenic genes. Similarly, fructose increased the abundance of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase mRNA, whereas GT significantly decreased its expression. GT did not alter the expression of scavenger receptor class B, type 1, microsomal TG transfer protein, and apobec 1 in the liver and intestine. The results suggest that the lipid-lowering effect of GT is mediated partly by its inhibition of hepatic lipogenesis involving SREBP-1c and its responsive genes without affecting lipoprotein assembly.

Raisins and additional walking have distinct effects on plasma lipids and inflammatory cytokines

BackgroundRaisins are a significant source of dietary fiber and polyphenols, which may reduce cardiovascular disease (CVD) risk by affecting lipoprotein metabolism and inflammation. Walking represents a low intensity exercise intervention that may also reduce CVD risk. The purpose of this study was to determine the effects of consuming raisins, increasing steps walked, or a combination of these interventions on blood pressure, plasma lipids, glucose, insulin and inflammatory cytokines.ResultsThirty-four men and postmenopausal women were matched for weight and gender and randomly assigned to consume 1 cup raisins/d (RAISIN), increase the amount of steps walked/d (WALK) or a combination of both interventions (RAISINS + WALK). The subjects completed a 2 wk run-in period, followed by a 6 wk intervention. Systolic blood pressure was reduced for all subjects (P = 0.008). Plasma total cholesterol was decreased by 9.4% for all subjects (P < 0.005), which was explained by a 13.7% reduction in plasma LDL cholesterol (LDL-C) (P < 0.001). Plasma triglycerides (TG) concentrations were decreased by 19.5% for WALK (P < 0.05 for group effect). Plasma TNF-α was decreased from 3.5 ng/L to 2.1 ng/L for RAISIN (P < 0.025 for time and group × time effect). All subjects had a reduction in plasma sICAM-1 (P < 0.01).ConclusionThis research shows that simple lifestyle modifications such as adding raisins to the diet or increasing steps walked have distinct beneficial effects on CVD risk.

A Plasma α-Tocopherome Can Be Identified from Proteins Associated with Vitamin E Status in School-Aged Children of Nepal

BACKGROUND The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations. OBJECTIVE To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 μmol/L). METHODS Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency. RESULTS We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability. CONCLUSIONS In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271.