Metabolic syndrome (MetS) represents a worldwide health problem, affecting cardiovascular and mental health. People with MetS are often suffering from depression. We used hereditary hypertriacylglycerolemic (HTG) rats as an animal model of MetS, and these were fed a high-fat-high-fructose diet (HFFD) to imitate unhealthy eating habits of people having several MetS risk factors and suffering depression. Male HTG rats were fed a standard diet (HTG-SD) or HFFD for eight weeks (HFFD8). Venlafaxine was administered for the last three weeks of the experiment (HFFD8+VE). Heart function was observed on the level of intact organisms (standard ECG in vivo), isolated hearts (perfusion according to Langendorff ex vivo), and molecular level, using the RT-PCR technique. The function of the isolated perfused heart was monitored under baseline and ischemia/reperfusion conditions. Analysis of ECG showed electrical abnormalities in vivo, such as significant QRS complex prolongation and increased heart rate. Ex vivo venlafaxine significantly reduced QT interval after ischemia/reperfusion injury. Baseline values of contractile abilities of the heart tended to be suppressed by HFFD. A significant reduction of LVDP was present in the HFFD8 group. Molecular analysis of specific genes involved in cardiac electrical (Cacna1c, Scn5a), contractile (Myh6, Myh7), metabolic function (Pgc1alpha) and calcium handling (Serca2a, Ryr2) supported some of the functional findings in vivo and ex vivo. Based on the present effect of venlafaxine on heart function, further research is needed regarding its cardiometabolic safety in the treatment of patients with MetS suffering from depression. Keywords: Metabolic syndrome, Venlafaxine, ECG, Cardiac contraction, Ischemia/Reperfusion.

• MeSH
• Diet, High-Fat * adverse effects   MeSH
• Fructose * adverse effects   administration & dosage   MeSH
• Hypertriglyceridemia * genetics   complications   drug therapy   MeSH
• Cardiovascular Diseases * etiology   prevention & control   MeSH
• Rats MeSH
• Metabolic Syndrome * drug therapy   physiopathology   MeSH
• Rats, Wistar MeSH
• Venlafaxine Hydrochloride * pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fructose * MeSH
• Venlafaxine Hydrochloride * MeSH

A high-fructose intake (HFI) in food, sweetened beverages, and soft drinks appears to be one of the risk factors that worsens human metabolic and cardiovascular health, although the more accurate mechanism remains unclear. Hypertriglyceridemic (HTG) rats represent a suitable animal model of metabolic syndrome where the consumption of an HFI could have an additional aggravating impact. We aimed to study the effect of fructose on the heart functions. Male HTG rats had HFI or a standard diet for five weeks. Heart function was tested ex vivo on the perfused heart using the Langendorff technique. Isolated hearts underwent 25 min ischemia (I) and 30 min reperfusion (R). Left ventricular developed pressure (LVDP), ventricular premature beats, and dysrhythmias were monitored during R. At the end of the R, ventricular fibrillation (VF) was evoked electrically. Systolic blood pressure, glucose level, serum total cholesterol (TC), triglycerides (TAG), and thiobarbituric acid reactive substances (TBARS) in the kidney were determined. The LVDP showed a reduced return to the input values, the duration of VF in R increased, and the threshold for VF induction decreased. Serum TC, TAG, and kidney TBARS were increased. The effect of HFI on heart ventricular impairment was associated with the reduced threshold for induction of VF and aggravated dyslipidemia. The results point to the adverse impact of dietary high-fructose intake in rats with hypertriglyceridemia.

• Keywords
• aortic endothelium-dependent relaxation, heart function, high-fructose intake, hypertriglyceridemic rats, lipid profile,
• MeSH
• Fructose * adverse effects   MeSH
• Hypertriglyceridemia * physiopathology   complications   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Rats, Wistar MeSH
• Heart * drug effects   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fructose * MeSH

OBJECTIVE: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

• MeSH
• Benzoxazoles MeSH
• Butyrates MeSH
• Fibric Acids therapeutic use   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Hypertriglyceridemia * drug therapy   MeSH
• Humans MeSH
• PPAR alpha metabolism   MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * therapeutic use   MeSH
• Triglycerides MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• (R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid MeSH Browser
• Benzoxazoles MeSH
• Butyrates MeSH
• Fibric Acids MeSH
• PPAR alpha MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * MeSH
• Triglycerides MeSH

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

• Keywords
• SGLT-2 inhibitors, cytochrome P450, empagliflozin, fatty liver, fetuin-A, lipid metabolism, oxidative stress,
• MeSH
• Benzhydryl Compounds pharmacology   MeSH
• Sodium-Glucose Transporter 2 Inhibitors pharmacology   MeSH
• Glucosides pharmacology   MeSH
• Hyperglycemia drug therapy   etiology   metabolism   MeSH
• Hyperlipoproteinemia Type IV complications   drug therapy   metabolism   MeSH
• Insulin Resistance MeSH
• Liver drug effects   metabolism   MeSH
• Rats MeSH
• Inflammation Mediators metabolism   MeSH
• Lipid Metabolism drug effects   MeSH
• Disease Models, Animal MeSH
• Rats, Mutant Strains MeSH
• Non-alcoholic Fatty Liver Disease etiology   metabolism   prevention & control   MeSH
• Obesity complications   metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Rats, Wistar MeSH
• Prediabetic State complications   drug therapy   metabolism   MeSH
• Disease Progression MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Benzhydryl Compounds MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides MeSH
• Inflammation Mediators MeSH
• Cytochrome P-450 Enzyme System MeSH

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.

• Keywords
• cell senescence, empagliflozin, hereditary hypertriglyceridemic rat model, hypertriglyceridemia, insulin sensitivity, metabolic syndrome,
• MeSH
• Administration, Oral MeSH
• Benzhydryl Compounds administration & dosage   MeSH
• 3T3-L1 Cells MeSH
• Hep G2 Cells MeSH
• Down-Regulation drug effects   MeSH
• Dyslipidemias drug therapy   MeSH
• Sodium-Glucose Transporter 2 Inhibitors administration & dosage   MeSH
• Gluconeogenesis drug effects   genetics   MeSH
• Glucosides administration & dosage   MeSH
• Weight Gain drug effects   MeSH
• Hypertriglyceridemia drug therapy   metabolism   MeSH
• Hypoglycemic Agents administration & dosage   MeSH
• Insulin Resistance MeSH
• Liver metabolism   MeSH
• Rats MeSH
• Kidney metabolism   MeSH
• Humans MeSH
• Lipogenesis drug effects   genetics   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Oxidative Stress drug effects   MeSH
• Cellular Senescence drug effects   MeSH
• Adipose Tissue metabolism   MeSH
• Up-Regulation drug effects   MeSH
• Cell Survival drug effects   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Benzhydryl Compounds MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides MeSH
• Hypoglycemic Agents MeSH

Background: To evaluate the association between hypertriglyceridemic waist (HTGW), a promising marker of visceral adiposity and cardiovascular (CV) risk, and different indicators of vascular damage in type 2 diabetes (T2D) patients. Methods: This case-control study included 161 patients with T2D (91 males, 70 females) and 40 healthy controls (24 males, 16 females). HTWG was defined as waist circumference >90 cm in men or >85 cm in women and triglyceride concentrations >2 mmol/L. In addition to anthropometric and metabolic parameters, markers of endothelial dysfunction, namely von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1), were assessed. Arterial stiffness parameters were examined using the SphygmoCor system. Results: Individuals with T2D and HTGW showed the highest elevation of PAI-1 levels and significantly increased vWF levels compared with healthy controls. No significant differences in arterial stiffness markers were observed between T2D individuals. Age and, for several markers, systolic and/or diastolic blood pressure were identified as the main predictors for arterial stiffness, whereas PAI-1 and vWF levels were predicted by metabolic parameters. Conclusions: HTGW represents increased CV risk in T2D patients, mainly due to endothelial damage. The presence of HTGW had no significant effect on arterial stiffness compared with other T2D individuals.

• Keywords
• arterial stiffness, hypertriglyceridemic waist, plasminogen activator inhibitor-1, type 2 diabetes, von Willebrand factor,
• MeSH
• Biomarkers blood   MeSH
• Diabetes Mellitus, Type 2 * epidemiology   MeSH
• Hypertriglyceridemic Waist * epidemiology   MeSH
• Plasminogen Activator Inhibitor 1 blood   MeSH
• Cardiovascular Diseases * blood   diagnosis   epidemiology   MeSH
• Humans MeSH
• Case-Control Studies MeSH
• von Willebrand Factor analysis   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Plasminogen Activator Inhibitor 1 MeSH
• von Willebrand Factor MeSH

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

• Keywords
• arachidonic acid, cytochrome P450, fatty acid profile, lipotoxic intermediates, metformin, myocardial function, myocardial phospholipids, stearoyl-CoA desaturase,
• MeSH
• Basal Metabolism drug effects   MeSH
• Biomarkers blood   MeSH
• Fatty Acid Desaturases metabolism   MeSH
• Hyperlipoproteinemia Type IV drug therapy   metabolism   MeSH
• Hypoglycemic Agents pharmacology   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Rats MeSH
• Arachidonic Acid metabolism   MeSH
• Inflammation Mediators blood   MeSH
• Lipid Metabolism drug effects   MeSH
• Metformin pharmacology   MeSH
• Disease Models, Animal MeSH
• Myocardium metabolism   MeSH
• Rats, Wistar MeSH
• Prediabetic State drug therapy   metabolism   MeSH
• Risk Factors MeSH
• Heart drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• Fatty Acid Desaturases MeSH
• Hypoglycemic Agents MeSH
• Cardiotonic Agents MeSH
• Arachidonic Acid MeSH
• Inflammation Mediators MeSH
• Metformin MeSH

Metabolic syndrome (MetS) is an important cause of worldwide morbidity and mortality. Its complex pathogenesis includes, on the one hand, sedentary lifestyle and high caloric intake, and, on the other hand, there is a clear genetic predisposition. PD (Polydactylous rat) is an animal model of hypertriglyceridemia, insulin resistance, and obesity. To unravel the genetic and pathophysiologic background of this phenotype, we compared morphometric and metabolic parameters as well as liver transcriptomes among PD, spontaneously hypertensive rat, and Brown Norway (BN) strains fed a high-fat diet (HFD). After 4 weeks of HFD, PD rats displayed marked hypertriglyceridemia but without the expected hepatic steatosis. Moreover, the PD strain showed significant weight gain, including increased weight of retroperitoneal and epididymal fat pads, and impaired glucose tolerance. In the liver transcriptome, we found 5480 differentially expressed genes, which were enriched for pathways involved in fatty acid beta and omega oxidation, glucocorticoid metabolism, oxidative stress, complement activation, triacylglycerol and lipid droplets synthesis, focal adhesion, prostaglandin synthesis, interferon signaling, and tricarboxylic acid cycle pathways. Interestingly, the PD strain, contrary to SHR and BN rats, did not express the Acsm3 (acyl-CoA synthetase medium-chain family member 3) gene in the liver. Together, these results suggest disturbances in fatty acid utilization as a molecular mechanism predisposing PD rats to hypertriglyceridemia and fat accumulation.

• Keywords
• Acsm3, high-fat diet, hypertriglyceridemia, insulin resistance, liver transcriptome, metabolic syndrome, polydactylous rat, spontaneously hypertensive rat,
• MeSH
• Diet, High-Fat adverse effects   MeSH
• Gene Expression MeSH
• Hypertriglyceridemia blood   genetics   MeSH
• Liver metabolism   MeSH
• Coenzyme A Ligases genetics   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Intra-Abdominal Fat metabolism   MeSH
• Polydactyly MeSH
• Rats, Inbred SHR MeSH
• Rats, Wistar MeSH
• Gene Expression Profiling methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acsm3 protein, rat MeSH Browser
• Coenzyme A Ligases MeSH

The aim of this study was to evaluate the mutual relationship among perivascular adipose tissue (PVAT) and endogenous and exogenous H2S in vasoactive responses of isolated arteries from adult normotensive (Wistar) rats and hypertriglyceridemic (HTG) rats, which are a nonobese model of metabolic syndrome. In HTG rats, mild hypertension was associated with glucose intolerance, dyslipidemia, increased amount of retroperitoneal fat, increased arterial contractility, and endothelial dysfunction associated with arterial wall injury, which was accompanied by decreased nitric oxide (NO)-synthase activity, increased expression of H2S producing enzyme, and an altered oxidative state. In HTG, endogenous H2S participated in the inhibition of endothelium-dependent vasorelaxation regardless of PVAT presence; on the other hand, aortas with preserved PVAT revealed a stronger anticontractile effect mediated at least partially by H2S. Although we observed a higher vasorelaxation induced by exogenous H2S donor in HTG rats than in Wistar rats, intact PVAT subtilized this effect. We demonstrate that, in HTG rats, endogenous H2S could manifest a dual effect depending on the type of triggered signaling pathway. H2S within the arterial wall contributes to endothelial dysfunction. On the other hand, PVAT of HTG is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of H2S. Nevertheless, the possible negative impact of PVAT during hypertriglyceridemia on the activity of exogenous H2S donors needs to be taken into consideration.

• Keywords
• H2S, HTG, Wistar, isolated artery, metabolic syndrome, perivascular adipose tissue,
• MeSH
• Aorta, Thoracic physiopathology   MeSH
• Endothelium, Vascular physiopathology   MeSH
• Cystathionine gamma-Lyase metabolism   MeSH
• Hypertriglyceridemia metabolism   MeSH
• Rats MeSH
• Metabolic Syndrome metabolism   physiopathology   MeSH
• Disease Models, Animal MeSH
• Norepinephrine pharmacology   MeSH
• Oxidation-Reduction MeSH
• Rats, Wistar MeSH
• Signal Transduction * MeSH
• Superoxide Dismutase metabolism   MeSH
• Superoxides metabolism   MeSH
• Nitric Oxide Synthase Type III metabolism   MeSH
• Adipose Tissue metabolism   MeSH
• Vasodilation physiology   MeSH
• Vasoconstriction drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cystathionine gamma-Lyase MeSH
• Norepinephrine MeSH
• Superoxide Dismutase MeSH
• Superoxides MeSH
• Nitric Oxide Synthase Type III MeSH

The history of studying hypertriglyceridemia as a risk factor for atherosclerosis has been going on for a half a century. The significance of this parameter as measured in fasting state is not entirely clear, since the statistical significance between triglyceride concentration and cardiovascular risk is lost after adjustment to HDL-cholesterol concentration. Remnant particles of chylomicrons and very low density lipoproteins measured postprandially appear to be responsible for the risk associated with hypertriglyceridemia. As the concentration of non-fasting triglycerides increases, the risk of myocardial infarction increases gradually up to five times.

• Keywords
• atherosclerosis risk, insulin resistance, liver, triglyceride,
• MeSH
• Atherosclerosis * complications   MeSH
• Cholesterol, HDL MeSH
• Hyperlipidemias * MeSH
• Hypertriglyceridemia * complications   MeSH
• Humans MeSH
• Risk Factors MeSH
• Triglycerides MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol, HDL MeSH
• Triglycerides MeSH