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

Hypolipidemic and cardioprotective effects of statins can be associated with the development of myopathies and new-onset type 2 diabetes. These adverse effects may be related to increased oxidative stress. The plant extract silymarin (SM) is known for its antioxidant and anti-inflammatory actions. We tested the hypothesis that the combination of atorvastatin (ATV) with SM could improve therapy efficacy and eliminate some negative effects of statin on hypertriglyceridemia-induced metabolic disorders. Hereditary hypertriglyceridemic rats were fed a standard diet for four weeks without supplementation; supplemented with ATV (5 mg/kg b. wt./day) or a combination of ATV with 1 % micronized SM (ATV+SM). ATV treatment elevated plasma levels of HDL-cholesterol (p<0.01), glucose and insulin and decreased triglycerides (p<0.001). The combination of ATV+SM led to a significant reduction in insulin, an improvement of glucose tolerance, and the hypolipidemic effect was enhanced compared to ATV alone. Furthermore, ATV supplementation increased skeletal muscle triglycerides but its combination with SM decreased triglycerides accumulation in the muscle (p<0.05) and the liver (p<0.01). In the liver, ATV+SM treatment increased the activities of antioxidant enzymes, glutathione and reduced lipid peroxidation (p<0.001). The combined administration of ATV with SM potentiated the hypolipidemic effect, reduced ectopic lipid accumulation, improved glucose metabolism, and increased antioxidant and anti-inflammatory actions. Our results show that SM increased the effectiveness of statin therapy in a hypertriglyceridemic rat model of metabolic syndrome.

• MeSH
• Anticholesteremic Agents adverse effects   MeSH
• Antioxidants pharmacology   MeSH
• Atorvastatin adverse effects   MeSH
• Diabetes Mellitus, Type 2 chemically induced   drug therapy   pathology   MeSH
• Hypercholesterolemia blood   MeSH
• Hyperlipidemias drug therapy   MeSH
• Drug Therapy, Combination MeSH
• Rats MeSH
• Metabolic Syndrome drug therapy   genetics   pathology   MeSH
• Disease Models, Animal MeSH
• Oxidative Stress drug effects   MeSH
• Silymarin pharmacology   MeSH
• Triglycerides blood   MeSH
• Inflammation drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anticholesteremic Agents MeSH
• Antioxidants MeSH
• Atorvastatin MeSH
• Silymarin MeSH
• Triglycerides 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

Excessive methylglyoxal (MG) production contributes to metabolic and vascular changes by increasing inflammatory processes, disturbing regulatory mechanisms and exacerbating tissue dysfunction. MG accumulation in adipocytes leads to structural and functional changes. We used transcriptome analysis to investigate the effect of MG on metabolic changes in the visceral adipose tissue of hereditary hypetriglyceridaemic rats, a non-obese model of metabolic syndrome. Compared to controls, 4-week intragastric MG administration impaired glucose tolerance (p < 0.05) and increased glycaemia (p < 0.01) and serum levels of MCP-1 and TNFα (p < 0.05), but had no effect on serum adiponectin or leptin. Adipose tissue insulin sensitivity and lipolysis were impaired (p < 0.05) in MG-treated rats. In addition, MG reduced the expression of transcription factor Nrf2 (p < 0.01), which controls antioxidant and lipogenic genes. Increased expression of Mcp-1 and TNFα (p < 0.05) together with activation of the SAPK/JNK signaling pathway can promote chronic inflammation in adipose tissue. Transcriptome network analysis revealed the over-representation of genes involved in insulin signaling (Irs1, Igf2, Ide), lipid metabolism (Nr1d1, Lpin1, Lrpap1) and angiogenesis (Dusp10, Tp53inp1).

• Keywords
• adipose tissue, insulin resistance, methylglyoxal,
• Publication type
• Journal Article MeSH

BACKGROUND: Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome-the Hereditary Hypertriglyceridaemic rats (HHTg). METHODS: Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks). RESULTS: Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01). CONCLUSION: Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.

• MeSH
• Glucose metabolism   MeSH
• Glycogen metabolism   MeSH
• Hydroxyethylrutoside analogs & derivatives   therapeutic use   MeSH
• Hypolipidemic Agents therapeutic use   MeSH
• Rats, Inbred Strains MeSH
• Insulin Resistance MeSH
• Muscle, Skeletal metabolism   MeSH
• Rats MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Metabolic Syndrome drug therapy   MeSH
• Lipid Metabolism drug effects   MeSH
• Disease Models, Animal MeSH
• Oxidative Stress drug effects   MeSH
• Transcriptome 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
• Glucose MeSH
• Glycogen MeSH
• Hydroxyethylrutoside MeSH
• Hypolipidemic Agents MeSH
• troxerutin MeSH Browser

BACKGROUND AND AIMS: Dicarbonyl stress plays an important role in the pathogenesis of microvascular complications that precede the formation of advanced glycation end products, and contributes to the development of renal dysfunction. In renal cells, toxic metabolites like methylglyoxal lead to mitochondrial dysfunction and protein structure modifications.In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in the model of metabolic syndrome. MATERIALS AND METHODS: Dicarbonyl stress was induced by intragastric administration of methylglyoxal (0.5 mg/kg bw for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats with insulin resistance and fatty liver. RESULTS: Methylglyoxal administration aggravated glucose intolerance (AUC0-120 p < 0.05), and increased plasma glucose (p < 0.01) and insulin (p < 0.05). Compared to controls, methylglyoxal-treated rats exhibited microalbuminuria (p < 0.01). Targeted proteomic analysis revealed increases in urinary secretion of pro-inflammatory parameters (MCP-1, IL-6, IL-8), specific collagen IV fragments and extracellular matrix proteins. Urine metabolomic biomarkers in methylglyoxal-treated rats were mainly associated with impairment of membrane phospholipids (8-isoprostane, 4-hydroxynonenal).Decreased levels of glutathione (p < 0.01) together with diminished activity of glutathione-dependent antioxidant enzymes contributed to oxidative and dicarbonyl stress. Methylglyoxal administration elevated glyoxalase 1 expression (p < 0.05), involved in methylglyoxal degradation. Based on comparative transcriptomic analysis of the kidney cortex, 96 genes were identified as differentially expressed (FDR < 0.05). Network analysis revealed an over-representation of genes related to oxidative stress and pro-inflammatory signalling pathways as well as an inhibition of angiogenesis suggesting its contribution to renal fibrosis. CONCLUSION: Our results support the hypothesis that dicarbonyl stress plays a key role in renal microvascular complications. At the transcriptome level, methylglyoxal activated oxidative and pro-inflammatory pathways and inhibited angiogenesis. These effects were further supported by the results of urinary proteomic and metabolomic analyses.

• Keywords
• Kidney dysfunction, Metabolic syndrome, Metabolomics, Methylglyoxal, Microvascular complications, Proteomics, Transcriptomics,
• Publication type
• Journal Article MeSH