👤 Andrew A Bremer

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both Show less

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all Show less

Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate the development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either a standard unpurified diet plus 75 g fructose/d (control group; n = 9) or a standard unpurified diet, 75 g fructose/d, and 4 g FO (16% EPA + 11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevented fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (Apo)C3, ApoE, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption. Show less

The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation. Show less

The use of embryonic stem cells is currently the most promising approach to assess developmental toxicity in vitro. In addition, the possibility of using human embryonic stem (hES) cells will increase safety of consumers and patients as false classification of substances due to inter-species variations can be avoided. One validated test based on murine embryonic stem cells, the embryonic stem cell test (EST), consists of following endpoints: IC(50) values of fibroblasts and embryonic stem cells as well as the inhibition of differentiation of mES cells into cardiomyocytes. As a follow up of its successful validation study we established a cytotoxicity assay based on hES cells and human fibroblasts employing two developmental toxicants: 5-fluorouracil (5-FU) and all-trans retinoic acid (RA). The results were compared to historical data from the EST. For 5-FU, no significant differences were obtained between the different cell lines. However, for RA, both test systems produced higher IC(50) values for the fibroblasts than for the stem cells, which is a well-known effect of developmental toxicants. Moreover, the reliability and relevance of several marker genes as possible toxicological endpoints were tested. During early differentiation Oct-4, hTert and Dusp6 showed the most reliable results. Brachyury and GATA-4 were found to be best suited to monitor cardiac differentiation. The late cardiac marker gene TNNT2 demonstrated significant results until day 18. Therefore, these marker genes have the highest potential to serve as endpoints for a developmental toxicity test. Show less