Fenofibrate prevents orotic acid--induced hepatic steatosis in rats.

The experiments performed in this report were designed to investigate the mechanisms involved in the metabolic alterations associated with orotic acid-induced hepatic steatosis and the effect of fenofibrate, a stimulant of peroxisome proliferators-activated receptor alpha (PPARalpha), on these alterations. Male Wistar rats were divided into three experimental groups: 1) fed a balanced diet (C); 2) fed a balanced diet supplemented with 1% orotic acid (OA); 3) fed OA diet containing 100 mg.kg(-1) bw.day(-1) fenofibrate (OA+F), for 9 days. Administration of OA to rats induced significant increase in the hepatic total lipids content, marked microvesicular steatosis and decrease in plasma lipids concentrations compared to control group. Fenofibrate treatment prevented fatty liver induction, caused an additional reduction on plasma lipids concentrations and caused a 40% decrease in the lipogenic rate in adipose tissue. The results also showed a 40% increase in lipoprotein lipase (LPL) activity in adipose tissue from OA treated group and fenofibrate administration induced a 50% decrease in LPL activity. The liver mRNA expression of PPARalpha and ACO (acyl CoA oxidase) were 85% and 68% decreased in OA group when compared to control, respectively. Fenofibrate treatment increased the PPARalpha and ACO expressions whereas the CPT-1 (carnitine palmitoyl transferase-1) expression was not altered. Our results have shown that fenofibrate treatment decreases the hepatic lipid content induced by OA which is mediated by an important increase in fatty acid oxidation consequent to an increase in hepatic mRNA expression of PPARalpha and ACO.

Increased expression of oxidative enzymes in adipose tissue following PPARα-activation.

OBJECTIVE: Evaluate the effect of fenofibrate treatment on the expression of PPARα and oxidative enzymes in adipose tissue. MATERIALS/METHODS: Wistar male rats were fed a balanced diet supplemented with 100mg.Kg-1 bw.day-1 fenofibrate (Sigma) during nine days. Plasma glucose, free fatty acids (FFA) leptin and insulin were determined. PPARα, ACO and CPT-1 mRNA expression and amount of PPARα and PPARγ protein were assessed in epididymal adipose tissue. Oral glucose tolerance test was evaluated into overnight fasted rats. Glucose uptake was measured in adipocytes isolated from epididymal fat pads in the presence or absence of insulin (25ng/mL). RESULTS: Fenofibrate treatment increased PPARα and PPARγ protein abundance in adipose tissue. In addition to it well- known effect on oxidative enzymes in liver, fenofibrate treatment also induces a high expression of Acyl CoA Oxidase (ACO) and Carnitine palmitoyltransferase 1 (CPT-1) in adipose tissue. Furthermore, we have shown that the fenofibrate treatment improves the glucose tolerance and enhance the glucose uptake by adipocytes. CONCLUSION: Altogether, the data suggest that fenofibrate have a direct effect in adipose tissue contributing to the low adiposity and improvement of glucose homeostasis.