Fenofibrate Decreases Hepatic P-Glycoprotein in a Rat Model of Hereditary Hypertriglyceridemia

P-glycoprotein (P-gp) is a membrane-bound transporter encoded by Mdr1a/Abcb1a and Mdr1b/Abcb1b genes in rodents involved in the efflux of cytotoxic chemicals and metabolites from cells. Modulation of its activity influences P-gp-mediated drug delivery and drug-drug interaction (DDI). In the current study, we tested the effects of fenofibrate on P-gp mRNA and protein content in non-obese model of metabolic syndrome. Males hereditary hypertriglyceridemic rats (HHTg) were fed standard laboratory diet (STD) (Controls) supplemented with micronized fenofibrate in lower (25 mg/kg b. wt./day) or in higher (100 mg/kg b. wt./day) dose for 4 weeks. Liver was used for the subsequent mRNA and protein content analysis. Fenofibrate in lower dose decreased hepatic Mdr1a by 75% and Mdr1b by 85%, while fenofibrate in higher dose decreased Mdr1a by 90% and Mdr1b by 92%. P-gp protein content in the liver was decreased by 74% in rat treated with fenofibrate at lower dose and by 88% in rats using fenofibrate at higher dose. These findings demonstrate for the first time that fenofibrate decreases both mRNA and protein amount of P-gp and suggest that fenofibrate could affect bioavailability and interaction of drugs used to treat dyslipidemia-induced metabolic disorders

Seriove triacylglyceroly a intravaskularni remodelovani HDL u cloveka

Increased triacylglycerols (TAG) in human plasma and low levels of HDL cholesterol are considered as significant risk factors of atherogenesis and labeled as "atherogenic couple". The term expresses the pathobiochemical context as well as the metabolic relationship of these two lipid parameters. The main aim of the study was to contribute to the problematics of metabolic interrelationships between serum lipoprotein TAG and HDL in human, focused on TAG lipolysis and consequent changes of HDL lipid components as involved in the determination of pathobiochemically important metabolic function of HDL. The model of enhanced intravascular TAG lipolysis and that of decelerated intravascular TAG lypolysis were made use of. Lipase release into the circulation provoked by heparin caused TAG lipolysis enhancement and was confirmed by a decrease of total and VLDL-TAG values, together with an increase of the molar ratio cholesterol/TAG in VDL. Heparin did not influence significantly the concentration of cholesterol in plasma or in individual lipoprotein fraction, due probably to the inhibitory effect of heparin on binding of plasma lipoproteins. In HDL, the distribution of TAG in HDL subfractions changed - a decrease in HDL_2 and an increase in HDL_3. The enhancement of lipolysis by hepatic lipase was related to the supply of HDL_2-TAG, to HDL_2 cholesterol decrease and to the lipid depletion of HDL_3 nucleus, and it could be involved in the formation of so-called "small" HDL with consequent deceleration of the reverse cholesterol transport. The results evidenced TAG distribution among HDL subfractions determined by activity of both lipases: HDL_3 can act as acceptors of non-lipolysed TAG during increased activity of hepatic lipase. These conclusions are supported by results of determination of Tag distribution between HDL_2 and HDL_3 in hyper- and hypoalphalipoproteinemia with hypertriglyceridemia. Oleic acid proportion in HDL was significantly higher in hypoalphalipoproteinemia and polyunsaturate acid proportion was lower than in hyperalphereby a prevention of the nosocomial infections that are often due to bacterial strains with a high level of resistanceAvailable from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Critical evaluation of colon submucosal microdialysis in awake, mobile rats

<div><p>Sensors able to record large bowel physiology and biochemistry <i>in situ</i> in awake rodents are lacking. Microdialysis is a mini-invasive technique that may be utilized to continuously deliver or recover low-molecular substances from various tissues. In this experiment we evaluated the feasibility of <i>in vivo</i> microdialysis to monitor extracellular fluid chemistry in the descending colon submucosa of conscious, freely moving rodents. Following surgical implantation of a microdialysis probe, male Wistar rats were housed in metabolic cages where they were analgized and clinically followed for four days with free access to standard diet and water. To assess local microcirculation and probe function, glucose, lactate, glucose-to-lactate ratio and urea clearance were determined in the dialysates from the three postoperative days with focus on the final 24-h period. In an attempt to mitigate the expected tissue inflammatory response, one group of animals had the catheters perfused with 5-aminosalicylic acid-enriched medium with final concentration 1 μmol/L. For verification of probe position and the assessment of the surrounding foreign body reaction, standard histological and immunohistochemical methods were employed. Microdialysis of rat gut is associated with considerable technical challenges that may lead to the loss of probe function and high drop-out rate. In this setting, limited data did not allow to draw any firm conclusion regarding local anti-inflammatory effectiveness of 5-aminosalicylic acid perfusion. Although intestinal microdialysis may be suitable for larger anesthetized animals, low reproducibility of the presented method compromises its routine experimental use in awake and freely moving small-sized rodents.</p></div

Routine biochemistry and hematology.

<p>Routine biochemistry and hematology.</p

Correlations between microdialysis parameters.

<p>Correlations between microdialysis parameters.</p

Experimental design.

<p>Sampling pattern reflected our interest in the fourth 24-h period (day 4). Information from preceding time periods was intentionally restricted to two solitary measurements.</p

Summary of experimental challenges.

<p>Summary of experimental challenges.</p

Animal physiology.

<p>Animal physiology.</p

Microdialysis data.

<p>Panels a-d depict data from three eligible animals (one from group A with perfusate A and two from group B with anti-inflammatory perfusate B). Data are displayed as individual measurements per time interval. RD_urea (%) was expressed as median (min-max) of values obtained on day 4. Symbols denote: *p<0.05 and **p<0.01 <i>vs</i>. rat A. Statistical approach was restricted to the evaluation of inter-individual differences owing to low number of subjects. Possible effect of 5-ASA (perfusate B) could not be determined. Due to ethical reasons the attempts to harvest more data were discontinued.</p

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes