Impact of Menopause and Body Composition Status on Dyslipidemia in Women.

Objective: The aim of this study was to identify the effects of menopausal and body composition statuses on measures of total and regional body composition and dyslipidemia in women. Methods: Sedentary, non-smoking women (N = 212), not currently treated for dyslipidemia were grouped based on 2 categories: (1) menstrual status: premenopausal or postmenopausal and (2) body composition status: normal weight (NW; BMI < 25 kg/m² and body fat (BF) < 36%), normal weight obese (NWO; BMI < 25 kg/m² and BF > 36%), or obese (BMI > 25 kg/m² and BF > 36%), to determine differences in total and regional body composition and measures of lipid and lipoprotein-cholesterol concentrations. Results: Overall, a greater prevalence of NWO was observed in postmenopausal versus premenopausal women. Being postmenopausal was associated with higher TC, LDL-C, non-HDL-C, HDL-C, and HDL3-C. Premenopausal NWO women had elevated LDL-C and VLDL-C comparable to obese women. Postmenopausal NWO women had elevated Tg and VLDL-C and lower HDL-C similar to obese women. Conclusions: Menopausal status was not associated with differences in fat distribution, however, the age-related differences in lipids and lipoproteins appear to be due to a difference in menopausal status exacerbated in women who are NWO.

Sperm-specific COX6B2 enhances oxidative phosphorylation, proliferation, and survival in human lung adenocarcinoma.

Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however, whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). COX6B2 is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD+ generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor-specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.

Mfsd2a and Glut1 Brain Nutrient Transporters Expression Increase with 32-Week Low and High Lard Compared with Fish-Oil Dietary Treatment in C57Bl/6 Mice.

BACKGROUND: Diet-mediated alterations of critical brain nutrient transporters, major facilitator super family domain-containing 2a (Mfsd2a) and glucose transporter 1 (Glut1), have wide reaching implications in brain health and disease. OBJECTIVE: The aim of the study was to examine the impact of long-term low- and high-fat diets with lard or fish oil on critical brain nutrient transporters, Mfsd2a and Glut1. METHODS: Eight-week-old male C57BL/6 mice were fed 1 of the following 4 diets for 32 wk: 10% of kcal from lard, 10% of kcal from fish oil, 41% of kcal from lard, or 41% of kcal from fish oil. Body weight and blood chemistries delineated dietary effects. Cortical and subcortical Mfsd2a and Glut1 mRNA and protein expression were evaluated, with other supportive nutrient-sensitive targets also assessed for mRNA expression changes. RESULTS: Fish-oil diets increased cortical Mfsd2a mRNA expression compared with lard diets. Subcortical Mfsd2a mRNA expression decreased as the percentage of fat in the diet increased. There was an interaction between the type and percentage of fat with cortical and subcortical Mfsd2a and cortical Glut1 protein expression. In the lard diet groups, protein expression of cortical and subcortical Mfsd2a and cortical Glut1 significantly increased as fat percentage increased. As the fat percentage increased in the fish-oil diet groups, protein expression of cortical and subcortical Mfsd2a and cortical Glut1 did not change. When comparing the fish-oil groups with 10% lard, cortical Mfsd2a protein expression was significantly higher in the 10% and 41% fish-oil groups, whereas cortical Glut1 protein expression was significantly higher in only the 10% fish-oil group. A positive correlation between cortical peroxisome proliferator-activated receptor γ mRNA expression and Mfsd2a protein expression was shown. CONCLUSION: Corresponding to chronic dietary treatment, an interaction between the type of fat and the percentage of fat exists respective to changes in brain expression of the key nutrient transporters Mfsd2a and Glut1.

Functional classification of long non-coding RNAs by k-mer content.

The functions of most long non-coding RNAs (lncRNAs) are unknown. In contrast to proteins, lncRNAs with similar functions often lack linear sequence homology; thus, the identification of function in one lncRNA rarely informs the identification of function in others. We developed a sequence comparison method to deconstruct linear sequence relationships in lncRNAs and evaluate similarity based on the abundance of short motifs called k-mers. We found that lncRNAs of related function often had similar k-mer profiles despite lacking linear homology, and that k-mer profiles correlated with protein binding to lncRNAs and with their subcellular localization. Using a novel assay to quantify Xist-like regulatory potential, we directly demonstrated that evolutionarily unrelated lncRNAs can encode similar function through different spatial arrangements of related sequence motifs. K-mer-based classification is a powerful approach to detect recurrent relationships between sequence and function in lncRNAs.

High-Fructose Intake Impairs the Hepatic Hypolipidemic Effects of a High-Fat Fish-Oil Diet in C57BL/6 Mice.

BACKGROUND: Overnutrition of saturated fats and fructose is one of the major factors for the development of nonalcoholic fatty liver disease. Because omega-3 polyunsaturated fatty acids (n-3fa) have established lipid lowering properties, we tested the hypothesis that n-3fa prevents high-fat and fructose-induced fatty liver disease in mice. METHODS: Male C57BL/6J mice were randomly assigned to one of the following diet groups for 14 weeks: normal diet (ND), high-fat lard-based diet (HFD), HFD with fructose (HFD + Fru), high-fat fish-oil diet (FOD), or FOD + Fru. RESULTS: Despite for the development of obesity and insulin resistance, FOD had 65.3% lower (P < 0.001) hepatic triglyceride levels than HFD + Fru, which was blunted to a 38.5% difference (P = 0.173) in FOD + Fru. The lower hepatic triglyceride levels were associated with a lower expression of lipogenic genes LXRα and FASN, as well as the expression of genes associated with fatty acid uptake and triglyceride synthesis, CD36 and SCD1, respectively. Conversely, the blunted hypotriglyceride effect of FOD + Fru was associated with a higher expression of CD36 and SCD1. CONCLUSIONS: During overnutrition, a diet rich in n-3fa may prevent the severity of hepatic steatosis; however, when juxtaposed with a diet high in fructose, the deleterious effects of overnutrition blunted the hypolipidemic effects of n-3fa.

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility.

Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain- or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosome-depleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.

Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer.

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFß signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFß signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology.

Resistance training reduces subclinical inflammation in obese, postmenopausal women.

PURPOSE: Aerobic exercise is frequently prescribed to reduce inflammatory-related disease (cardiovascular disease and diabetes) risk. Resistance training (RT), however, may be key to maximizing anti-inflammatory benefits of consistent exercise. We examined the influence of RT on inflammatory biomarkers in obese, postmenopausal women. METHODS: Twenty-three women (65.6 ± 2.6 yr; body mass index, 33 kg·m) underwent 12 wk of RT (3 sets, 10 exercises, 3× per week, 8-12 repetition maximum (RM), resistance exercise (EX), N = 11) or social interaction intervention (SI, stretching, knitting, health lectures, 2× per week, control group (CON), N = 12). Both before (BT) and after (AT) RT or SI, blood was collected before (PR), immediately (PO), 2 h (2H), and 24 h (24H) after a single resistance exercise bout (RE) in EX and at the same time points in nonexercise, resting CON. For all time points, blood was analyzed for IL-6, leptin, and lipopolysaccharide (LPS)-stimulated tumor necrosis factor-α (TNF-α) (LPS-TNF) and IL-10 (LPS-IL10). PR samples were also examined for C-reactive protein, TNF-α, and adiponectin, and mRNA expression of toll-like receptor 4 (TLR4) and MC1R. Subcutaneous adipose tissue was extracted BT and AT and analyzed for mRNA expression of monocyte chemotactic protein-1, leptin, CD68, and TLR4. RESULTS: RT improved strength (44%) and reduced circulating C-reactive protein (-33%), leptin (-18%) and TNF-α (-29%) with no change in body composition. IL-6 decreased after SI in CON (-17%). LPS-TNF increased after SI or RT (CON +26%, EX +67%, respectively), whereas LPS-IL10 decreased in CON (-28%) but increased in EX (+20%). RT did not influence inflammatory biomarker gene expression in whole blood or subcutaneous adipose tissue. A single RE bout augmented LPS-TNF and LPS-IL10 at 24H in EX, particularly AT. CONCLUSION: RT reduced markers of subclinical inflammation in circulation in obese, postmenopausal women in the absence of changes in body composition. Chronic RT also enhanced response to endotoxin challenge both at rest (PR) and 24 h after an acute RE bout (24H).

A single 1-h session of moderate-intensity aerobic exercise does not modify lipids and lipoproteins in normolipidemic obese women.

The purpose of this study was to quantify the effects of a single session of aerobic exercise on lipids and lipoproteins in women who were sedentary and obese. Women (n = 12) who were premenopausal, sedentary, and obese (body mass index, 30-40 kg·m(-2); waist circumference > 88 cm) completed exercise and control trials in a randomly assigned order. Exercise consisted of a single session of treadmill walking at 70% maximum oxygen uptake until 500 kcal were expended, and the control protocol consisted of 60 min of seated rest. Fasting blood samples were collected immediately prior to, 24 h, and 48 h following the exercise and control sessions and analyzed for triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL(2)-C, and HDL(3)-C concentrations, and mean LDL, HDL(2), and HDL(3) particle size and cholesterol distributions. A 2 × 3 (trial × time) ANOVA with repeated measures revealed no significant (p > 0.05) changes in the lipid and lipoprotein variables 24 and 48 h following exercise. In contrast to previously published data in lean men and women, a single session of treadmill exercise at 70% maximum oxygen uptake that expended 500 kcal was insufficient to modify lipids and lipoproteins in women who were sedentary, normolipidemic, and obese.