Association of EDARV370A with breast density and metabolic syndrome in Latinos

The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.

Postprandial Lipid Metabolism in Normolipidemic Subjects and Patients with Mild to Moderate Hypertriglyceridemia: Effects of Test Meals Containing Saturated Fatty Acids, Mono-Unsaturated Fatty Acids, or Medium-Chain Fatty Acids

Fasting and postprandial hypertriglyceridemia are causal risk factors for atherosclerosis. The prevalence of hypertriglyceridemia is approximately 25–30% and most hypertriglyceridemic patients suffer from mild to moderate hypertriglyceridemia. Data regarding dietary interventions on postprandial triglyceride metabolism of mildly to moderately hypertriglyceridemic patients is, however, sparse. In a randomized controlled trial, eight mildly hypertriglyceridemic patients and five healthy, normolipidemic controls received three separate standardized fat-meals containing either saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), or medium-chain fatty acids (MCFA) in a randomized order. Fasting and postprandial lipid parameters were determined over a 10 h period and the (incremental) area under the curve (AUC/iAUC) for plasma triglycerides and other parameters were determined. MCFA do not lead to a significant elevation of postprandial total plasma triglycerides and other triglyceride parameters, while both SFA (patients: p = 0.003, controls: p = 0.03 compared to MCFA) and MUFA (patients: p = 0.001; controls: p = 0.14 compared to MCFA) do lead to such an increase. Patients experienced a significantly more pronounced increase of plasma triglycerides than controls (SFA: patients iAUC = 1006 mg*h/dL, controls iAUC = 247 mg*h/dL, p = 0.02; MUFA: patients iAUC = 962 mg*h/dL, controls iAUC = 248 mg*h/dL, p = 0.05). Replacing SFA with MCFA may be a treatment option for mildly to moderately hypertriglyceridemic patients as it prevents postprandial hypertriglyceridemia.

A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice

Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is potential alternative to other ANGPTL3-inhibiting therapies.HighlightsANGPTL3 and ANGPTL4 are mediators of lipoprotein metabolism that inhibit lipoprotein lipase (LPL) activity.Vaccination using virus-like particles (VLPs) targeting ANGPTL3 and ANGPTL4 elicits high-titer IgG antibody responses.Immunization with ANGPTL3 VLPs lowers steady-state plasma triglycerides and enhances LPL activity.

Acute Effect of Coconut Oil on Peak Forearm Blood Flow in Healthy Men: A Randomized Crossover Trial

Background: A high-fat meal can induce vascular dysfunction. Despite containing a high amount of saturated fats, coconut oil is claimed to have cardiovascular health benefits. However, the information regarding the acute effect of coconut oil on vascular function in humans is unknown. Objective: To determine the effects of coconut oil ingestion experiment (Coco) on peak forearm blood flow (FBFpeak) and plasma biomarkers in healthy subjects. Materials and Methods: Seventeen healthy young men completed two separate experimental visits, Coco and control experiment (Con) in random order. The outcomes were FBFpeak measured by venous occlusion plethysmography and biomarkers as plasma triglycerides, free fatty acids, and malondialdehyde. The outcomes were collected at baseline (12 hour fasting), 2-hour and 4-hour after Coco (45 mL) in the Coco visit and at the same timeline in the control visit. Statistical analyses were performed to compare the data between the two experimental groups and within the group. Results: FBFpeak at 4-hour was significantly increased from the baseline (24.2±4.7 versus 21.7±3.8 mL/100 mL tissue.minute, p=0.009). Plasma triglycerides at 2-hour (75±25 mg/dL, p=0.03) and 4-hour (72±22 mg/dL, p=0.039) were significantly increased from the baseline (65±20 mg/dL). Coco significantly increased plasma free fatty acids at 2-hour (125.1±60.3 μEq/L, p=0.042) and at 4-hour (166.9±35.3 μEq/L, p<0.001) compared to the baseline (87.2±34.0 μEq/L). There were no significant changes in vascular resistance and plasma malondialdehyde. Conclusion: Coconut oil augmented vascular function in healthy young men by increasing FBFpeak despite the accompanying postprandial elevations of plasma triglycerides and free fatty acids. Keywords: Virgin coconut oil, Peak forearm blood flow, Vascular function, Saturated fatty acid, Medium chain triglyceride

High Fat-High Fructose Diet-Induced Changes in the Gut Microbiota Associated with Dyslipidemia in Syrian Hamsters

Aim: The objective of this study was to characterize the early effects of high fructose diets (with and without high fat) on both the composition of the gut microbiota and lipid metabolism in Syrian hamsters, a reproducible preclinical model of diet-induced dyslipidemia. Methods: Eight-week-old male hamsters were fed diets consisting of high-fat/high-fructose, low-fat/high-fructose or a standard chow diet for 14 days. Stool was collected at baseline (day 0), day 7 and day 14. Fasting levels of plasma triglycerides and cholesterol were monitored on day 0, day 7 and day 14, and nonfasting levels were also assayed on day 15. Then, 16S rRNA sequencing of stool samples was used to determine gut microbial composition, and predictive metagenomics was performed to evaluate dietary-induced shifts in deduced microbial functions. Results: Both high-fructose diets resulted in divergent gut microbiota composition. A high-fat/high-fructose diet induced the largest shift in overall gut microbial composition, with dramatic shifts in the Firmicute/Bacteroidetes ratio, and changes in beta diversity after just seven days of dietary intervention. Significant associations between genus level taxa and dietary intervention were identified, including an association with Ruminococceace NK4A214 group in high-fat/high-fructose fed animals and an association with Butryimonas with the low-fat/high-fructose diet. High-fat/high-fructose feeding induced dyslipidemia with increases in plasma triglycerides and cholesterol, and hepatomegaly. Dietary-induced changes in several genus level taxa significantly correlated with lipid levels over the two-week period. Differences in microbial metabolic pathways between high-fat/high-fructose and low-fat/high-fructose diet fed hamsters were identified, and several of these pathways also correlated with lipid profiles in hamsters. Conclusions: The high-fat/high-fructose diet caused shifts in the host gut microbiota. These dietary-induced alterations in gut microbial composition were linked to changes in the production of secondary metabolites, which contributed to the development of metabolic syndrome in the host.

Novel Association between Gemfibrozil and Dyslipidemia: A Case Report

Dyslipidemia is a risk factor in many health complications, among them is hypertension. Case: This report presents a case of a poorly controlled dyslipidemia that could not be managed by medications. A surprisingly and an unexpected factor interfered; the triglyceride-lowering medication caused a significant increase in the appetite toward fat-rich food items which opposed its intended purpose. Methodology: A dietary intervention and an uncommon drug dose modification were necessary. Results: The personally designed protocol led to a significant overall improvement and was successful in adjusting the biochemical parameters especially the plasma triglycerides and the total cholesterol and was effective in reversing hypertension and a pre-diabetic state to safer values. Conclusion: This is the first characterized case in the literature on the involvement of gemfibrozil in poor management of dyslipidemia.