Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

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 P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques

Synthesis of the oxysterol, 24(S), 25-epoxycholesterol, parallels cholesterol production and may protect against cellular accumulation of newly-synthesized cholesterol

AIM: The effects of 24(S),25-epoxycholesterol (24,25EC) on aspects of cholesterol homeostasis is well-documented. When added to cells, 24,25EC decreases cholesterol synthesis and up-regulates cholesterol efflux genes, including ABCA1. Synthesis of 24,25EC occurs in a shunt of the mevalonate pathway which also produces cholesterol. Therefore, 24,25EC synthesis should be subject to the same negative feedback regulation as cholesterol synthesis. To date, no role has been ascribed to 24,25EC in light of the fact that increased accumulation of cholesterol should decrease formation of this oxysterol through feedback inhibition. This leads to the intriguing paradox: why inhibit production of an apparently important regulator of cholesterol homeostasis when it is needed most? METHODS: We used a combination of pharmacological and genetic approaches in Chinese Hamster Ovary cell-lines to investigate this paradox. Endogenous synthesis of 24,25EC was manipulated using partial inhibition of the enzyme, Oxidosqualene Cyclase. Changes in cholesterol and 24,25EC synthesis were determined using metabolic labelling with [1-(14)C]-acetate, thin-layer chromatography and phosphorimaging. Transcriptional effects mediated via SREBP and LXR were analysed by luciferase reporter assays. RESULTS: We showed that cholesterol addition to cells lead to a rapid and preferential inhibition of 24,25EC synthesis. Addition of 24,25EC resulted in parallel inhibition of 24,25EC and cholesterol synthesis. Furthermore, we used a variety of approaches to examine the relationship between cholesterol and 24,25EC synthesis, including cell-lines with different rates of cholesterol synthesis, varying cholesterol synthetic rates by pre-treatment with a statin, or lipoprotein cholesterol loading of macrophages. In all cases, we showed that 24,25EC synthesis faithfully tracked cholesterol synthesis. Moreover, changes in 24,25EC synthesis exerted downstream effects, reducing SREBP transcriptional activity whilst increasing ABCA1 and LXR transcriptional activity. CONCLUSION: Our results show that 24,25EC synthesis parallels cholesterol synthesis, consistent with this oxysterol functioning as a safety valve to protect against the accumulation of newly-synthesised cholesterol (as opposed to exogenously-derived cholesterol). Considering that 24,25EC is capable of being produced in all cholesterogenic cells, we propose that production of 24,25EC may represent a ubiquitous defence mechanism

Is Seladin-1 really a selective Alzheimer\u27s disease indicator?

Selective Alzheimer\u27s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer\u27s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD

Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning

Sonic hedgehog (Shh) acts as a morphogen to mediate the specification of distinct cell identities in the ventral neural tube through a Gli-mediated (Gli1-3) transcriptional network. Identifying Gli targets in a systematic fashion is central to the understanding of the action of Shh. We examined this issue in differentiating neural progenitors in mouse. An epitope-tagged Gli-activator protein was used to directly isolate cis-regulatory sequences by chromatin immunoprecipitation (ChIP). ChIP products were then used to screen custom genomic tiling arrays of putative Hedgehog (Hh) targets predicted from transcriptional profiling studies, surveying 50-150 kb of non-transcribed sequence for each candidate. In addition to identifying expected Gli-target sites, the data predicted a number of unreported direct targets of Shh action. Transgenic analysis of binding regions in Nkx2.2, Nkx2.1 (Titf1) and Rab34 established these as direct Hh targets. These data also facilitated the generation of an algorithm that improved in silico predictions of Hh target genes. Together, these approaches provide significant new insights into both tissue-specific and general transcriptional targets in a crucial Shh-mediated patterning process

THE EFFECTS OF ULTRA-FILTERED MILK CONSUMPTION ON STRENGTH AND PERFORMANCE FOLLOWING RESISTANCE TRAINING IN FEMALE COLLEGIATE ATHLETES

Resistance training is beneficial in the improvement of skeletal muscle functionality. Improvements in performance, increased resistance to injury, and great force production are associated with resistance training. Hypertrophy of skeletal muscle mass is important for improving fitness, decreasing body fat percentage, improvements in whole-body metabolism, and enhancements in quality of life. The ability to recovery properly following subsequent training sessions is critical for maximizing training adaptations. Nutrient supplementation has been previously studied. The supplementation of carbohydrates has been shown to replenish muscle glycogen stores. The consumption of carbohydrates following resistance training benefits muscle protein balance by attenuating muscle protein breakdown. Another commonly consumed supplement is amino acids/protein. Supplementation of protein has demonstrated improvements in body composition (i.e. increased fat free mass), increases in hypertrophy, and muscular strength. Two type of proteins used by individuals that resistance train are whey protein and casein protein. Whey protein is a fast digesting protein that leads to quick stimulation of protein synthesis. Casein protein is a slower digesting protein that also attenuates the breakdown of muscle protein. Milk is a natural product that contains carbohydrates, whey protein, and casein protein. Whole milk, low fat milk (i.e., 1-2%), and fat free milk have shown positive results in the ability to improve muscle protein synthesis, lean body mass, strength gains. Therefore, the purpose of the following dissertation is to compare the effects of higher protein, less sugar content chocolate milk to traditional low fat chocolate milk on adaptations to (1) strength and performance measures and (2) body composition following resistance training

Susceptibility of streptozotocin-induced diabetic rat retinal function and ocular blood flow to acute intraocular pressure challenge.

PURPOSE. To consider the hypothesis that streptozotocin (STZ)-induced hyperglycemia renders rat retinal function and ocular blood flow more susceptible to acute IOP challenge. METHODS. Retinal function (electroretinogram [ERG]) was measured during acute IOP challenge (10-100 mm Hg, increments of 5 mm Hg, 3 minutes per step, vitreal cannulation) in adult Long-Evans rats (6 weeks old; citrate: n ¼ 6, STZ: n ¼ 10) 4 weeks after citrate buffer or STZ (65 mg/kg, blood glucose >15 mM) injection. At each IOP, dim and bright flash (À4.56, À1.72 log cd.s.m À2 ) ERG responses were recorded to measure inner retinal and ON-bipolar cell function, respectively. Ocular blood flow (laser Doppler flowmetry; citrate: n ¼ 6, STZ: n ¼ 10) was also measured during acute IOP challenge. Retinas were isolated for quantitative PCR analysis of nitric oxide synthase mRNA expression (endothelial, eNos; inducible, iNos; neuronal, nNos). CONCLUSIONS. STZ-induced diabetes increased functional susceptibility during acute IOP challenge. This functional vulnerability is associated with a reduced capacity for diabetic eyes to upregulate eNos expression and to autoregulate blood flow in response to stress. (Invest Ophthalmol Vis Sci. RESULTS. STZ-induced diabetes increase

Laboratory Evaluation of the Formosan Subterranean Termite Resistance of Borate-treated Rubberwood Chipboard

Both no-choice and two-choice 4-week AWPA laboratory tests were performed to evaluate the resistance of borate-treated rubberwood (Hevea brasiliensis) chipboard prepared from a commercial mill run, against the Formosan subterranean termite Coptotermes formosanus. Boric acid (technical granular) was incorporated into the boards during manufacture to achieve loadings of 1.0% or 1.1% boric acid equivalents (BAE). In the no-choice test, both the untreated chipboard and solid rubberwood controls sustained heavy termite attack (respective mean visual ratings of 4.6 and 2.7 on a 10- point AWPA scale), while the two retentions of borate-treated chipboard showed only light grazing (mean rating 9.2). The two-choice test demonstrated a preference of termites for solid rubberwood (mean rating 2.4) instead of untreated chipboard (rating 8.4), and for untreated (mean rating 8.4 and 8.8) instead of borate-treated (mean ratings 9.8 & 9) chipboards. Complete termite mortality in the presence of borate-treated chipboard in both laboratory tests demonstrates the toxicity of borates to Formosan subterranean termites

Resistance of Borate-Treated Rubberwood Chipboard to the Formosan Subterranean Termite (lsoptera: Rhinotermitidae)

Both no-choice and two-choice 4-week AWPA laboratory tests were performed to evaluate the resistance of borate-treated rubberwood (Hevea brasiliensis) chipboard prepared from a commercial mill run, against the Formosan subterranean termite Coptotermes fonnosanus. Boric acid (technical granular) was incorporated into the boards during manufacture to achieve loadings of 1.0% or 1.1% boric acid equivalents (BAE). In the no-choice test, both the untreated chipboard and solid rubberwood controls sustained heavy termite attack (respective mean visual ratings of 4.6 and 2.7 on a 10-pointAWPA scale). while the two retentions of borate-treated chipboard showed only light grazing (mean rating 9.2). The two-choice test demonstrated a preference of termites for solid rubberwood (mean rating 2.4) instead of untreated chipboard (rating 8.4), and for untreated (mean rating 8.4 and 8.8) instead of borate-treated (mean ratings 9.8 & 9) chipboards. Complete termite mortality in the presence ofborate-treated chipboard in both laboratory tests demonstrates the toxicity of borates to Formosan subterranean termites