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.

• 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

• MeSH
• Angiopoietin-like Proteins antagonists & inhibitors   genetics   MeSH
• Angiopoietin-Like Protein 3 MeSH
• Oligonucleotides, Antisense therapeutic use   MeSH
• Apolipoprotein C-III * antagonists & inhibitors   genetics   MeSH
• Hypertriglyceridemia drug therapy   genetics   metabolism   MeSH
• Cardiovascular Diseases drug therapy   genetics   metabolism   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Triglycerides antagonists & inhibitors   genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Introduction: The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. Results: Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P < 0.01). HHTg animals exhibited qualitative changes in NEFA fatty acid composition, represented by an increased proportion of saturated fatty acids (P < 0.05) and a decreased proportion of n-3 PUFA (P < 0.01). Ectopic lipid deposition in the kidneys of HHTg rats-triglycerides (+30%) and cholesterol (+10%)-was associated with markedly elevated microalbuminuria as ageing increased, despite the absence of microalbuminuria at the young age of 3 months in these animals. According to targeted proteomic analysis, 3-month-old HHTg rats (in comparison to age-matched controls) exhibited increased urinary secretion of proinflammatory parameters (MCP-1, IL-6, IL-8, P < 0.01) and decreased urinary secretion of epidermal growth factor (EGF, P < 0.01) before manifestation of microalbuminuria. Elevation in the urinary secretion of inflammatory cytokines can be affected by increased relative expression of MCP-1 in the renal cortex (P < 0.05). Conclusions: Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.

• MeSH
• Albuminuria etiology   urine   MeSH
• Urinalysis MeSH
• Biomarkers blood   urine   MeSH
• Early Diagnosis MeSH
• Time Factors MeSH
• Cytokines urine   MeSH
• Epidermal Growth Factor urine   MeSH
• Hypertriglyceridemia blood   complications   genetics   urine   MeSH
• Lipids blood   MeSH
• Inflammation Mediators urine   MeSH
• Metabolic Syndrome blood   complications   genetics   urine   MeSH
• Disease Models, Animal MeSH
• Kidney Diseases blood   etiology   urine   MeSH
• Rats, Transgenic MeSH
• Rats, Wistar MeSH
• Predictive Value of Tests MeSH
• Proteomics * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Plasma triglyceride (TG) values are significant predictors of cardiovascular and total mortality. The plasma levels of TGs have an important genetic background. We analyzed whether 32 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies are discriminators of hypertriglyceridemia (HTG) in the Czech population. OBJECTIVES: The objective of this study was to replicate and test the original findings in an independent study and to re-analyze the gene score leading to HTG. METHODS: In total, we analyzed 32 SNPs in 209 patients with plasma TG levels over 10 mmol/L (HTG group) and compared them in a case-control design with 524 treatment-naïve controls (normotriglyceridemic [NTG] group) with plasma TG values below 1.8 mmol/L. RESULTS: Sixteen SNPs were significantly associated with an increased risk of HTG development, with odds ratios (ORs) (95% confidence interval [CI]) varying from 1.40 (1.01-1.95) to 4.69 (3.29-6.68) (rs964184 within the APOA5 gene). Both unweighted (sum of the risk alleles) and weighted gene scores (WGS) (log of the achieved ORs per individual genotype) were calculated, and both gene scores were significantly different between groups. The mean score of the risk alleles was significantly increased in the HTG group compared to the NTG group (18.5 ± 2.5 vs. 15.7 ± 2.3, respectively; P < 0.00001). Subjects with a WGS over 9 were significantly more common in the HTG group (44.5%) than in the NTG group, in which such a high score was observed in only 4.7% of subjects (OR 16.3, 95% CI 10.0-36.7; P < 0.0000001). CONCLUSIONS: An increased number of risk genetic variants, calculated both in a weighted or unweighted manner, significantly discriminates between the subjects with HTG and controls. Population-specific sets of SNPs included into the gene score seem to yield better discrimination power.

• MeSH
• Alleles MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Association Studies * methods   MeSH
• Genetic Testing MeSH
• Genotype MeSH
• Hypertriglyceridemia blood   diagnosis   epidemiology   genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Comorbidity MeSH
• Middle Aged MeSH
• Humans MeSH
• Odds Ratio MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

The risk of development of metabolic syndrome can be increased by hypertriglyceridemia. A search for effective therapy is a subject of considerable attention. Therefore, our hypothesis is that the fish oil (containing polyunsaturated fatty acids; n-3 PUFA) in a combination with silymarin can more effectively protect against hypertriglyceridemia-induced metabolic disturbances. The study was conducted using a unique non-obese strain of rats with hereditary hypertriglyceridemia an accepted model of metabolic syndrome. Adult male rats were treated with n-3 PUFA (300 mg/kg/day) without or with 1 % micronized silymarin in a diet for 4 weeks. The treatment with the diet containing n-3 PUFA and silymarin significantly reduced concentrations of serum triglycerides (-45 %), total cholesterol (-18 %), non-esterified fatty acids (-33 %), and ectopic lipid accumulation in skeletal muscle (-35 %) compared to controls. In addition, an increase in Abcg5 and Abcg8 mRNA expression (as genes affecting lipid homeostasis) as well as in protein content of ABCG5 (+78 %) and ABCG8 (+232 %) transporters have been determined in the liver of treated rats. Our findings suggest that this combined diet could be used in the prevention of hypertriglyceridemia-induced metabolic disorders.

• MeSH
• Antioxidants metabolism   MeSH
• Diet * MeSH
• Dyslipidemias therapy   MeSH
• Gene Expression drug effects   MeSH
• Hypertriglyceridemia complications   drug therapy   genetics   MeSH
• Rats MeSH
• Lipids blood   MeSH
• Metabolic Syndrome etiology   prevention & control   MeSH
• Lipid Metabolism drug effects   genetics   MeSH
• Disease Models, Animal MeSH
• Fatty Acids, Omega-3 administration & dosage   MeSH
• Oxidative Stress drug effects   MeSH
• Lipid Peroxidation drug effects   MeSH
• Rats, Wistar MeSH
• Fish Oils MeSH
• Silymarin administration & dosage   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.

• MeSH
• Sterol O-Acyltransferase biosynthesis   genetics   MeSH
• Gene Expression MeSH
• Fructose administration & dosage   adverse effects   MeSH
• Hypertriglyceridemia chemically induced   genetics   metabolism   MeSH
• Liver drug effects   metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Plasma triglyceride (TG) levels represent a significant risk factor of cardiovascular and total mortality. Concentrations of TG in the plasma depend, to a large extent, on the genetic background, and the apolipoprotein A5 (APOA5) gene seems to be one of the most powerful players in the plasma TG metabolism regulation. In total, we analysed three tagging APOA5 (rs964184 rs662799, rs3135506) SNPs in 209 patients with plasma TG levels over 10 mmol/l (HTG) on at least one occasion and in 379 treatment-naïve controls (NTG) with plasma TG values within the normal range. Minor alleles of all three analysed APOA5 polymorphisms significantly (all P < 0.0001) increased the risk of hypertriglyceridaemia. The most significant association (P < 0.0000001) was observed for the rs964184 polymorphism, where the minor GG homozygotes had the odds ratio (OR, 95% CI) for hypertriglyceridaemia development 21.30 (8.09-56.07, P < 0.000001) in comparison with the major CC allele homozygotes. Carriers of at least one minor allele at rs3135506 had OR (95% CI) 4.19 (2.75-6.40); (P < 0.000005) for HTG development and similarly, carriers of a minor allele at rs662799 had OR (95% CI) 3.07 (2.00-4.72) (P < 0.0001). The cumulative presence of risk alleles (unweighted gene score) significantly differed between patients with episodes of high TG and controls at P < 0.0000001. There were 73 % of subjects without any of the risk alleles among the controls and 46 % in the patients. In contrast, the controls just included 3 % of subjects with score 3 and more in comparison with 18 % in HTG patients. We conclude that common APOA5 variants are very important genetic determinants of episodic hypertriglyceridaemia in the Czech population with a high potential to be applied in personalized medicine.

• MeSH
• Alleles MeSH
• Apolipoprotein A-V genetics   MeSH
• Adult MeSH
• Gene Frequency genetics   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Genotype MeSH
• Haplotypes genetics   MeSH
• Hypertriglyceridemia blood   genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Triglycerides blood   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Parallel glucose measurements in blood and other different tissues give us knowledge about dynamics of glycemia changes, which depend on vascularization, distribution space and local utilization by tissues. Such information is important for the understanding of glucose homeostasis and regulation. The aim of our study was to determine the time-lag between blood, brain, and adipose tissue during rapid glucose changes in a male hHTG rat (n=15). The CGMS sensor Guardian RT (Minimed/Medtronic, USA) was inserted into the brain and into the abdominal subcutaneous tissue. Fixed insulin and variable rate of glucose infusion was used to maintain euglycemia during sensor calibration period. At 0 min, 0.5 g/kg of bolus of glucose was administered, and at 50 min, 5 IU/kg of bolus of insulin was administered. Further glucose and insulin infusion was stopped at this time. The experiment was finished at 130 min and animals were euthanized. The time-shift between glycemia changes in blood, brain, and subcutaneous tissue was calculated by identification of the ideal correlation function. Moreover, the time to achieve 90 % of the maximum glucose excursion after intervention (T90) was measured to compare our data with the literature. The time-lag blood vs. brain and blood vs. subcutaneous tissue was 10 (10; 15) min and 15 (15; 25) min, respectively. The difference was statistically significant (P=0.01). T90 after glucose bolus in brain and subcutaneous tissue was 10 min (8.75; 15) and 15 min (13.75; 21.25), respectively. T90 after insulin bolus in brain and subcutaneous tissue was 10 min (10; 15) and 20 min (20; 27.5), respectively. To the contrary, with literature, our results showed earlier glucose level changes in brain in comparison with subcutaneous tissue after glucose and insulin boluses. Our results suggest that glucose dynamics is different within monitored tissues under rapid changing glucose level and we can expect similar behavior in humans. Improved knowledge about glucose distribution and dynamics is important for avoiding hypoglycemia.

• MeSH
• Glycemic Index physiology   MeSH
• Hypertriglyceridemia blood   diagnosis   genetics   MeSH
• Blood Glucose metabolism   MeSH
• Rats MeSH
• Monitoring, Physiologic methods   trends   MeSH
• Brain metabolism   MeSH
• Rats, Wistar MeSH
• Subcutaneous Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Reactive dicarbonyls stimulate production of advanced glycation endproducts, increase oxidative stress and inflammation and contribute to the development of vascular complications. We measured concentrations of dicarbonyls - methylglyoxal (MG), glyoxal (GL) and 3-deoxyglucosone (3-DG) - in the heart and kidney of a model of metabolic syndrome - hereditary hypertriglyceridemic rats (HHTg) and explored its modulation by metformin. Adult HHTg rats were fed a standard diet with or without metformin (300 mg/kg b.w.) and dicarbonyl levels and metabolic parameters were measured. HHTg rats had markedly elevated serum levels of triacylglycerols (p<0.001), FFA (p<0.01) and hepatic triacylglycerols (p<0.001) along with increased concentrations of reactive dicarbonyls in myocardium (MG: p<0.001; GL: p<0.01; 3-DG: p<0.01) and kidney cortex (MG: p<0.01). Metformin treatment significantly reduced reactive dicarbonyls in the myocardium (MG: p<0.05, GL: p<0.05, 3-DG: p<0.01) along with increase of myocardial concentrations of reduced glutathione (p<0.01) and glyoxalase 1 mRNA expression (p<0.05). Metformin did not have any significant effect on dicarbonyls, glutathione or on glyoxalase 1 expression in kidney cortex. Chronically elevated hypertriglyceridemia was associated with increased levels of dicarbonyls in heart and kidney. Beneficial effects of metformin on reactive dicarbonyls and glyoxalase in the heart could contribute to its cardioprotective effects.

• MeSH
• Deoxyglucose analogs & derivatives   metabolism   MeSH
• Diet MeSH
• Stress, Physiological MeSH
• Glutathione metabolism   MeSH
• Glyoxal metabolism   MeSH
• Hypertriglyceridemia drug therapy   genetics   physiopathology   MeSH
• Hypoglycemic Agents therapeutic use   MeSH
• Rats MeSH
• Lactoylglutathione Lyase metabolism   MeSH
• Metformin therapeutic use   MeSH
• Myocardium metabolism   MeSH
• Rats, Wistar MeSH
• Pyruvaldehyde metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Diet, Fat-Restricted MeSH
• Child MeSH
• Hepatomegaly MeSH
• Hypertriglyceridemia genetics   metabolism   MeSH
• Humans MeSH
• Lipoprotein Lipase genetics   deficiency   MeSH
• Pancreatitis MeSH
• Prognosis MeSH
• Splenomegaly MeSH
• Lipid Metabolism, Inborn Errors * enzymology   MeSH
• Xanthomatosis MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Case Reports MeSH