Background: Hypertriglyceridemia has serious health risks such as cardiovascular disease, type 2 diabetes mellitus, nephropathy, and others. Fenofibrate is an effective hypolipidemic drug, but its benefits for ameliorating disorders associated with hypertriglyceridemia failed to be proven in clinical trials. Methods: To search for possible causes of this situation and possibilities of their favorable influence, we tested the effect of FF monotherapy and the combination of fenofibrate with silymarin on metabolic disorders in a unique model of hereditary hypertriglyceridemic rats (HHTg). Results: Fenofibrate treatment (100 mg/kg BW/day for four weeks) significantly decreased serum levels of triglyceride, (-77%) and free fatty acids (-29%), the hepatic accumulation of triglycerides, and the expression of genes encoding transcription factors involved in lipid metabolism (Srebf2, Nr1h4. Rxrα, and Slco1a1). In contrast, the hypertriglyceridemia-induced ectopic storage of lipids in muscles, the heart, and kidneys reduced glucose utilization in muscles and was not affected. In addition, fenofibrate reduced the activity of the antioxidant system, including Nrf2 expression (-35%) and increased lipoperoxidation in the liver and, to a lesser extent, in the kidneys and heart. Adding silymarin (micronized form, 600 mg/kg BW/day) to fenofibrate therapy increased the synthesis of glycogen in muscles, (+36%) and reduced hyperinsulinemia (-34%). In the liver, it increased the activity of the antioxidant system, including PON-1 activity and Nrf2 expression, and reduced the formation of lipoperoxides. The beneficial effect of combination therapy on the parameters of oxidative stress and lipoperoxidation was also observed, to a lesser extent, in the heart and kidneys. Conclusions: Our results suggest the potential beneficial use of the combination of FF with SLM in the treatment of hypertriglyceridemia-induced metabolic disorders.

• Keywords
• fenofibrate, glycogen synthesis, insulin resistance, metabolic syndrome, oxidative stress, reesterification of fatty acids, silymarin, triglycerides,
• Publication type
• Journal Article MeSH

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.

• Keywords
• lipidome, lipids, n-3 fatty acids, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis,
• MeSH
• Cholesterol metabolism   MeSH
• Choline metabolism   MeSH
• Diet, High-Fat adverse effects   MeSH
• Liver metabolism   MeSH
• Fatty Acids, Nonesterified metabolism   MeSH
• Methionine metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease * etiology   genetics   MeSH
• Fatty Acids, Unsaturated metabolism   MeSH
• Fatty Acids, Omega-3 * pharmacology   therapeutic use   metabolism   MeSH
• Racemethionine metabolism   pharmacology   MeSH
• Triglycerides metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• Choline MeSH
• Fatty Acids, Nonesterified MeSH
• Methionine MeSH
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 * MeSH
• Racemethionine MeSH
• Triglycerides 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

BACKGROUND: Several members of connexin family of transmembrane proteins were previously implicated in distinct metabolic conditions. In this study we aimed to determine the effects of complete and heterozygous form of connexin50 gene (Gja8) mutation L7Q on metabolic profile and oxidative stress parameters in spontaneously hypertensive inbred rat strain (SHR). METHODS: Adult, standard chow-fed male rats of SHR, heterozygous SHR-Dca+/- and SHR-Dca-/- coisogenic strains were used. At the age of 4 months, dexamethasone (2.6 μg/ml) was administered in the drinking water for three days. The lipidemic profile (cholesterol and triacylglycerol concentration in 20 lipoprotein fractions, chylomicron, VLDL, LDL and HDL particle sizes) together with 33 cytokines and hormones in serum and several oxidative stress parameters in plasma, liver, kidney and heart were assessed. RESULTS: SHR and SHR-Dca-/- rats had similar concentrations of triacylglycerols and cholesterol in all major lipoprotein fractions. The heterozygotes reached significantly highest levels of total (SHR-Dca+/-: 51.3 ± 7.2 vs. SHR: 34.5 ± 2.4 and SHR-Dca-/-: 34.4 ± 2.5 mg/dl, p = 0.026), chylomicron and VLDL triacylglycerols. The heterozygotes showed significantly lowest values of HDL cholesterol (40.9 ± 2.3 mg/dl) compared both to SHR (51.8 ± 2.2 mg/dl) and SHR-Dca-/- (48.6 ± 2.7 mg/dl). Total and LDL cholesterol in SHR-Dca+/- was lower compared to SHR. Glucose tolerance was improved and insulin concentrations were lowest in SHR-Dca-/- (1.11 ± 0.20 pg/ml) in comparison with both SHR (2.32 ± 0.49 pg/ml) and SHR-Dca+/- (3.04 ± 0.21 pg/ml). The heterozygous rats showed profile suggestive of increased oxidative stress as well as highest serum concentrations of several pro-inflammatory cytokines including interleukins 6, 12, 17, 18 and tumor necrosis factor alpha. CONCLUSIONS: Our results demonstrate that connexin50 mutation in heterozygous state affects significantly the lipid profile and the oxidative stress parameters in the spontaneously hypertensive rat strain.

• Keywords
• Animal models, Connexin, Lipoprotein, Metabolic syndrome, Oxidative stress,
• MeSH
• Cholesterol blood   MeSH
• Cytokines blood   MeSH
• Heterozygote * MeSH
• Insulin blood   MeSH
• Connexins genetics   MeSH
• Rats MeSH
• Metabolic Syndrome blood   genetics   metabolism   MeSH
• Mutation, Missense * MeSH
• Oxidative Stress MeSH
• Rats, Inbred SHR MeSH
• Triglycerides blood   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• connexin 50 MeSH Browser
• Cytokines MeSH
• Insulin MeSH
• Connexins MeSH
• Triglycerides MeSH

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease.

• Keywords
• Animal model, High-fat diet, Methionine- and choline-deficient diet, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Otsuka-Long-Evans-Tokushima fatty rats, Zucker rats,
• MeSH
• Species Specificity MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Liver Cirrhosis metabolism   pathology   physiopathology   MeSH
• Liver metabolism   pathology   physiopathology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Non-alcoholic Fatty Liver Disease * etiology   genetics   metabolism   pathology   physiopathology   MeSH
• Nutritional Status MeSH
• Disease Progression MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

• MeSH
• Anti-Inflammatory Agents pharmacology   therapeutic use   MeSH
• Antioxidants pharmacology   therapeutic use   MeSH
• C-Reactive Protein genetics   MeSH
• Fumarates pharmacology   therapeutic use   MeSH
• Hemodynamics drug effects   MeSH
• Rats MeSH
• Humans MeSH
• Metabolic Syndrome drug therapy   genetics   metabolism   physiopathology   MeSH
• Oxidative Stress drug effects   MeSH
• Rats, Inbred SHR MeSH
• Transcriptome drug effects   MeSH
• Inflammation drug therapy   genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Antioxidants MeSH
• C-Reactive Protein MeSH
• Fumarates MeSH

BACKGROUND: The role of folate deficiency and associated hyperhomocysteinemia in the pathogenesis of metabolic syndrome is not fully established. In the current study, we analyzed the role of folate deficiency in pathogenesis of the metabolic syndrome in the spontaneously hypertensive rat (SHR). METHODS: Metabolic and hemodynamic traits were assessed in SHR/Ola rats fed either folate-deficient or control diet for 4 weeks starting at the age of 3 months. RESULTS: Compared to SHRs fed a folate-replete diet, SHRs fed a folate-deficient diet showed significantly reduced serum folate (104 ± 5 vs. 11 ± 1 nmol/L, P < 0.0005) and urinary folate excretion (4.3 ± 0.6 vs. 1.2 ± 0.1 nmol/16 h, P < 0.0005) together with a near 3-fold increase in plasma total homocysteine concentration (4.5 ± 0.1 vs 13.1 ± 0.7 μmol/L, P < 0.0005), ectopic fat accumulation in liver, and impaired glucose tolerance. Folate deficiency also increased systolic blood pressure by approximately 15 mm Hg (P < 0.01). In addition, the low-folate diet was accompanied by significantly reduced activity of antioxidant enzymes and increased concentrations of lipoperoxidation products in liver, renal cortex, and heart. CONCLUSIONS: These findings demonstrate that the SHR model is susceptible to the adverse metabolic and hemodynamic effects of low dietary intake of folate. The results are consistent with the hypothesis that folate deficiency can promote oxidative stress and multiple features of the metabolic syndrome that are associated with increased risk for diabetes and cardiovascular disease.

• MeSH
• Hyperhomocysteinemia etiology   MeSH
• Hypertension etiology   MeSH
• Insulin Resistance physiology   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Folic Acid metabolism   MeSH
• Metabolic Syndrome etiology   MeSH
• Folic Acid Deficiency complications   MeSH
• Oxidative Stress * MeSH
• Glucose Intolerance etiology   MeSH
• Rats, Inbred SHR MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Folic Acid MeSH

CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long-chain fatty acids (FA). Previously, we found that the spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene that results in reduced transport of long-chain FA into cardiomyocytes and predisposes the SHR to cardiac hypertrophy. In the current study, we analyzed the effects of mutant Cd36 on susceptibility to ischemic ventricular arrhythmias and myocardial infarction in adult SHR-Cd36 transgenic rats with wild-type Cd36 compared with age-matched SHR controls. Using an open-chest model of coronary artery occlusion, we found that SHR-Cd36 transgenic rats showed profound arrhythmogenesis resulting in significantly increased duration of tachyarrhythmias (207 ± 48 s vs. 55 ± 21 s, P < 0.05), total number of premature ventricular complexes (2,623 ± 517 vs. 849 ± 250, P < 0.05) and arrhythmia score (3.86 ± 0.18 vs. 3.13 ± 0.13, P < 0.001). On the other hand, transgenic SHR compared with SHR controls showed significantly reduced infarct size (52.6 ± 4.3% vs. 72.4 ± 2.9% of area at risk, P < 0.001). Similar differences were observed in isolated perfused hearts, and the increased susceptibility of transgenic SHR to arrhythmias was abolished by reserpine, suggesting the involvement of catecholamines. To further search for possible molecular mechanisms of altered ischemic tolerance, we compared gene expression profiles in left ventricles dissected from 6-wk-old transgenic SHR vs. age-matched controls using Illumina-based sequencing. Circadian rhythms and oxidative phosphorylation were identified as the top KEGG pathways, while circadian rhythms, VDR/RXR activation, IGF1 signaling, and HMGB1 signaling were the top IPA canonical pathways potentially important for Cd36-mediated effects on ischemic tolerance. It can be concluded that transgenic expression of Cd36 plays an important role in modulating the incidence and severity of ischemic and reperfusion ventricular arrhythmias and myocardial infarct size induced by coronary artery occlusion. The proarrhythmic effect of Cd36 transgene appears to be dependent on adrenergic stimulation.

• MeSH
• CD36 Antigens genetics   metabolism   MeSH
• Genetic Predisposition to Disease MeSH
• Myocardial Infarction genetics   metabolism   pathology   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Rats, Inbred SHR MeSH
• Arrhythmias, Cardiac genetics   metabolism   MeSH
• Gene Expression Profiling * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• CD36 Antigens MeSH

Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHRs) in which we transgenically expressed human CRP in the liver under control of the apolipoprotein E promoter. In transgenic SHRs, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10 to 15 mm Hg greater in transgenic SHRs expressing human CRP than in SHR controls (P<0.01). During oral glucose tolerance testing, transgenic SHRs exhibited hyperinsulinemia compared with controls (insulin area under the curve: 36±7 versus 8±2 nmol/L per 2 hours, respectively; P<0.05). Transgenic SHRs also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol of glucose per gram per 2 hours; P<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L; P<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L; P<0.05), and microalbuminuria (200±35 versus 26±5 mg of albumin per gram of creatinine, respectively; P<0.001). Transgenic SHRs had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (36.4±5.2 versus 18±1.7 pg/mL; P<0.005) and increased hepatic and renal thiobarbituric acid reactive substances (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nmol/L per milligram of protein, respectively; P<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.

• MeSH
• Adiponectin metabolism   MeSH
• Analysis of Variance MeSH
• C-Reactive Protein genetics   metabolism   MeSH
• Glucose Tolerance Test MeSH
• Insulin metabolism   MeSH
• Blood Glucose metabolism   MeSH
• Blood Pressure genetics   MeSH
• Rats MeSH
• Humans MeSH
• Metabolic Syndrome etiology   genetics   metabolism   MeSH
• Oxidative Stress genetics   MeSH
• Rats, Inbred SHR MeSH
• Rats, Transgenic MeSH
• Telemetry MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adiponectin MeSH
• C-Reactive Protein MeSH
• Insulin MeSH
• Blood Glucose MeSH