Tosca L. Zern

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.

Weight Loss Favorably Modifies Anthropometrics and Reverses the Metabolic Syndrome in Premenopausal Women

Objective: To determine the effects of a weight loss program, including dietary modifications, increased physical activity and dietary supplement (L-carnitine or placebo) on anthropometrics, leptin, insulin, the metabolic syndrome (MS) and insulin resistance in overweight /obese premenopausal women. Methods: Participants consumed a hypocaloric diet; 30% protein, 30% fat and 40% carbohydrate in addition to increasing number of steps/day. Carnitine supplementation followed a randomized double blind protocol. Protocol lasted for 10 weeks. Seventy subjects (35 in the control and 35 in the carnitine group) completed the intervention. Anthropometrics, plasma insulin and leptin concentrations and body composition were measured. The number of subjects with the MetSyn and insulin resistance, were assessed at baseline and post-intervention. Results: Because there were no significant differences between the carnitine and the placebo groups for all measured parameters, participants were grouped together for all analysis. Subjects decreased total energy (−26.6%, p < 0.01) and energy from carbohydrate (−17.3%, p < 0.01) and increased energy from protein by 67% (p < 0.01) and number of steps/day (42.6%, p < 0.01). Body weight (−4.6%, p < 0.001), body mass index (−4.5%, p < 0.01), waist circumference (−6.5%, p < 0.01), total fat mass (−1.7%, p < 0.01), trunk fat mass (−2.0%, p < 0.01), insulin (− 17.9%, p < 0.01) and leptin (−5.9%, p < 0.05) decreased after the intervention. Ten of 19 participants with insulin resistance became insulin sensitive and 7 of 8 participants with the MetSyn no longer had the syndrome after the intervention. Conclusion: Moderate increases in physical activity and a hypocaloric/high protein diet resulted in multiple beneficial effects on body anthropometrics and insulin sensitivity. Realistic dietary and physical activity goals must be the focus of intervention strategies for overweight and obese individuals.

Habitual consumption of eggs does not alter the beneficial effects of endurance training on plasma lipids and lipoprotein metabolism in untrained men and women

Changes in plasma lipid and apolipoprotein profiles were evaluated in 12 healthy, unfit subjects (VO(2peak) 39.1+/-2.8 ml.kg(-1).min(-1); 5 women, 7 men) at baseline and following endurance exercise training. The exercise protocol consisted of a 6-week endurance exercise training program (4-5 days week(-1); 60 min.session(-1); > or =65% HR(max)). Subjects were randomly assigned to consume an egg- (n=6; 12 eggs.week(-1)) or no-egg (n=6; 0 eggs.week(-1))-based, eucaloric, standardized diet for 8 weeks. Both diets were macronutrient balanced [60% carbohydrate, 30% fat, 10% protein (0.8 g.kg(-1).day(-1))] and individually designed for weight maintenance. Plasma lipids were measured twice within the same week at baseline and following exercise training. At baseline, subjects were normolipidemic with values of 163.9+/-41.8, 84.8+/-36.7, 60.6+/-15.4 and 93.1+/-52 mg dl(-1) for total cholesterol, LDL cholesterol and HDL cholesterol and triglyceride concentrations, respectively. A two-way ANOVA was used to analyze diet and exercise effects and interactions. In both groups, endurance exercise training resulted in a significant 10% increase in HDL-C (P<.05), a 19% decrease in Apo B concentrations (P<.05) and reductions in plasma CETP activity (P<.05). Plasma LDL-C decreased by 21% (P=.06). No main effects of diet or interactions with plasma lipids or Apo B concentrations were observed. These data demonstrate that endurance training improved the plasma lipid profiles of previously unfit, normolipidemic subjects independent of dietary cholesterol intake from eggs.

Replacing dietary carbohydrate with protein and fat decreases the concentrations of small LDL and the inflammatory response induced by atherogenic diets in the guinea pig

Guinea pigs resemble humans in cholesterol and lipoprotein metabolism; however, there is limited information on the vascular inflammatory response with induction of atherosclerosis in this animal model. The purpose of this study was to document a vascular inflammatory response associated with dietary-induced atherosclerosis in the guinea pig and determine the effect of replacing dietary carbohydrate with protein and fat on this response. Thirty male Hartley guinea pigs were randomly assigned to a high dietary cholesterol, high-carbohydrate (HC); a high-cholesterol, low-carbohydrate (LC) or a control (CON) diet for 12 weeks. Analysis of cytokine protein expression [interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 and GM-CSF) and m RNA expression (IFN-γ, TNF-α, IL-1β, MCP-1 and IL-8] were performed along with the measurement of cholesterol concentration in the aorta, plasma lipids and plasma low-density lipoprotein subfractions. There was a similar and significant accumulation of cholesterol in the thoracic aorta in the HC and LC groups compared to the CON group. Aortic cytokine protein expression (TNF-α, IFN-γ and IL-6) and m RNA expression (TNF-α and IFN-γ) were significantly elevated in both high-cholesterol fed groups (HC and LC) (P<.05) compared to the CON group. Compared to the HC group, animals fed the LC diet had reduced protein and m RNA TNF-α expression, as well as a reduced concentration of small LDL particles in the plasma. This study is the first to document a dietary cholesterol-induced vascular inflammatory response in guinea pigs that is partially regulated by the macronutrient content of the diet. Guinea pigs may be a useful animal model to evaluate the cellular and molecular components of atherosclerosis.