To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these levels to the severity of insulin resistance. Ceramides are a putative mediator resistance lipotoxicity, accumulation ceramides within tissues diabetic has been well described.

Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver (NAFLD). Since plasma ceramides are increased NAFLD and sphingomyelin, ceramide metabolite, an independent risk factor for CVD, the role of dyslipidemia was assessed using LDLR-/- mice, diet-induced model atherosclerosis. Mice were fed standard or Western diet (WD), with without myriocin, inhibitor synthesis. Hepatic profiled lipid lipoprotein kinetics quantified. intestinal expression genes proteins involved...

Key points Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results reduced skeletal mitochondrial respiration, electron transport chain complex I dysfunction, as well lower NAD + /NADH ratio ATP content. During hyperammonaemia, leak electrons from III oxidative modification proteins lipids. Tricarboxylic acid cycle intermediates are decreased during providing a cell‐permeable ester αKG reversed the TCA...

Nonalcoholic fatty liver disease (NAFLD) is a common that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). So far, the underlying mechanism remains poorly understood. Here, we show hepatic carboxylesterase 2 (CES2) markedly reduced in NASH patients, diabetic db/db mice, and high-fat diet (HFD)-fed mice. Restoration of CES2 expression or HFD-fed mice ameliorates insulin resistance. In contrast, knockdown causes damage chow- Western diet-fed C57BL/6 Mechanistically,...

Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine impact pharmacological activation by INT-767 on reversal diet-induced disorders, and relative contribution FXR vs. TGR5 INT-767's effects parameters. Wild-type (WT), Tgr5−/−, Fxr−/−, Apoe−/− Shp−/− mice were used investigate whether how BA INT-767, a semisynthetic agonist for both TGR5, could reverse disorders. reversed...

Objective To assess the effect of exercise training on insulin sensitivity and plasma ceramides in obesity type 2 diabetes (T2D). Methods Twenty-four adults with normal glucose tolerance (NGT, n = 14) or (n 10) were studied before after a 12-week supervised exercise-training program (5 days/week, 1 h/day, 80-85% maximum heart rate). Changes body composition assessed using hydrostatic weighing computed tomography. Peripheral tissue was by 40 mU/m2/min hyperinsulinemic euglycemic clamp. Plasma...

Abstract Background The relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate cognitive decline in mild impairment (MCI) dementia stages Alzheimer’s disease (AD) is unknown. role peripheral cerebrospinal fluid (CSF) levels Apolipoprotein A1 (ApoA1), a key functional component HDL, also remains unclear among them. Here we evaluate baseline TG/HDL-C ratio CSF ApoA1 their relation with MCI Dementia AD....

Bariatric surgery is associated with near immediate remission of type 2 diabetes and hyperlipidemia. The mechanisms underlying restoration normal glucose tolerance postoperatively are poorly understood. Herein, we examined the effect Roux‐en‐Y gastric bypass (RYGB) on weight loss, insulin sensitivity, plasma ceramides, proinflammatory markers, cardiovascular risk factors before at 3 6 months after surgery. Thirteen patients (10 female; age 48.5 ± 2.7 years; BMI, 47.4 1.5 kg/m ) were included...

Traditional proteomics provides static assessment of protein content, but not synthetic rates. Recently, proteome dynamics with heavy water ((2)H2O) was introduced, where (2)H labels amino acids that are incorporated into proteins, and the synthesis rate individual proteins is calculated using mass isotopomer distribution analysis. We refine this approach a novel algorithm rigorous selection criteria improve accuracy precision calculation rates use it to measure kinetics in spatially...

Hyperglycemia plays a key role in the pathogenesis of cardiovascular complications diabetes. Type 2 diabetes mellitus (T2DM) is associated with high-density lipoprotein (HDL) dysfunction and increased degradation apolipoprotein I (ApoAI). The mechanism(s) these changes largely unknown. To study hyperglycemia-induced glycation on ApoAI kinetics stability patients diet-controlled T2DM. 2H2O-metabolic labeling approach was used to turnover T2DM [n = 9 (5 F); 59.3 ± 8.5 years] matched healthy...

Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-metabolic labeling approach to test hypothesis that stability of oxidative phosphorylation proteins contributes in a diet-induced mouse model NAFLD. A high fat diet containing cholesterol (a so-called Western (WD)) led stress, steatosis, inflammation and mild fibrosis, all markers NAFLD, low density (LDL) receptor deficient (LDLR−/−) mice....

Abstract Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate crises in PA patients by accelerating the breakdown of odd-chain fatty acids amino into propionyl-CoA, direct evidence is lacking. Our investigation effects -/- (A138T) mice, a model, reveals surprising outcomes. Propionylcarnitine, biomarker, decreases during fasting, along with C3/C2...

Proteomics investigations typically yield information regarding static gene expression profiles. The central issues that limit the study of proteome dynamics include how to (i) administer a labeled amino acid in vivo, (ii) measure isotopic labeling protein(s) (which may be low), and (iii) reliably interpret precursor/product relationships. In this study, we demonstrate potential quantifying by coupling administration stable isotopes with mass spectrometric assays. Although direct acid(s) is...

Patients with cirrhosis have increased gluconeogenesis and fatty acid oxidation that may contribute to a low respiratory quotient (RQ), this be linked sarcopenia metabolic decompensation when these patients are hospitalized. Therefore, we conducted prospective study measure RQ its impact on skeletal muscle mass, survival, related complications in hospitalized cirrhotic patients. Fasting resting energy expenditure (REE) were determined by indirect calorimetry ( n = 25), age, sex,...

Metabolic labeling with heavy water followed by LC–MS is a high throughput approach to study proteostasis in vivo. Advances mass spectrometry and sample processing have allowed consistent detection of thousands proteins at multiple time points. However, freely available automated bioinformatics tools analyze extract protein decay rate constants are lacking. Here, we describe d2ome—a robust, software solution for vivo turnover analysis. d2ome highly scalable, uses innovative approaches...

We have studied the accretion of lipids in growing mice. measured rates synthesis and degradation triglycerides epididymal fat pads mice maintained for 44 days on a low-fat, high-carbohydrate diet (I) or high-fat, low-carbohydrate (II). 2H2O was added to drinking water 14 days. Rates incorporation/washout 2H to/from C1 triglyceride-glycerol showed that triglyceride greater than (net balance approximately 2.5 times II I). The data also show contribution de novo lipogenesis triglyceride-bound...

4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C9, C6) or drugs abuse (C4, C5). We investigated the catabolism these compounds using a combination metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations unlabeled labeled saturated 4-hydroxyacids (C4 to C11) 4-hydroxynonenal. All tested form new class acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem spectrometry, accurate 31P-NMR. five...