FENOFIBRATE MODIFIES TRANSAMINASE GENE-EXPRESSION VIA A PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA-DEPENDENT PATHWAY

Fibrates modify the expression of genes implicated in lipoprotein and fatty acid metabolism via the peroxisome proliferator-activated recept or alpha(PPAR alpha), leading to reductions in serum triglycerides and cholesterol. The expression of certain penes regulated by PPAR alpha have been shown to be modified in a species dependent manner. Aspartat e aminotransferase (AspAT or GOT) and alanine aminotransferase (AlaAT or GPT) are enzymes involved in intermediate metabolism in all cells a nd in hepatic gluconeogenesis. These enzymes are also widely used as s erum markers of possible tissue damage. This study investigated whethe r fenofibrate could modify the expression of liver AspAT and:or AlaAT and thus possibly alter transaminase levels independently of a cytotox ic effect. In human Hep G2 cells. fenofibrate increased cytosolic AspA T (cAspAT) activity by 40% and AlaAT activity by 100%, as well as both mRNAs. Nuclear run on assays showed that this effect was, at least in part, transcriptional. Increases in mRNA were also observed in human hepatocyte cultures at concentrations of the drug attained in patients . In C57BL/6 mice, Fenofibrate decreased cAspAT and cAlaAT mRNA. while these effects were abolished in PPAR alpha knock-out mice. In conclus ion. fenofibrate has been shown to modify cAspAT and AlaAT gene expres sion in a species and PPAR alpha dependent manner. This is the first d emonstration that cAspAT and AlaAT activities may be pharmacologically altered, independently of a toxic phenomenon. (C) 1998 Elsevier Scien ce Ireland Ltd. All rights reserved.