Mechanism for peroxisome proliferator-activated receptor-alpha activator-induced up-regulation of UCP2 mRNA in rodent hepatocytes.

Peroxisome proliferator-activated receptor-alpha (PPARalpha)activators, fish oil feeding, or fibrate administration up-regulated mitochondrial uncoupling protein (UCP2) mRNA expression in mouse liver by 5-9-fold, whereas tumor necrosis factor-alpha (TNFalpha) also up-regulated UCP2 in liver. In this study, the mechanisms for PPARalpha activators-induced up-regulation of UCP2 mRNA, related to TNFalpha and reactive oxygen species (ROS), were investigated. PPARalpha activators-induced UCP2 up-regulation in mouse/rat liver tissues was due to their increases in hepatocytes but not in non-parenchymal cells. Addition of PPARalpha activators, WY14,643 or fenofibrate, to cultured hepatocytes up-regulated UCP2 mRNA by 5-10-fold. PPARalpha activators-induced up-regulation of UCP2 mRNA was not due to increased mRNA stability and required cycloheximide-sensitive short term turnover protein(s). However, expression of PPARalpha/retinoid X receptor-alpha and PGC-1 was not rate-limiting for WY14,643-induced UCP2 up-regulation. In primary hepatocytes, an exogenous oxidant, tert-butyl-hydroperoxide (TBHP), which increased ROS production, up-regulated UCP2 mRNA, whereas WY14,643 treatment did not produce detectable ROS under the condition that fibrate markedly up-regulated UCP2. In in vivo studies, PPARalpha activators moderately up-regulated TNFalpha mRNA expression in mouse liver. An anti-oxidant pyrrolidine dithiocarbamate ammonium salt injection completely prevented their TNFalpha mRNA increases but did not prevent most of their UCP2 mRNA increases. These data indicate that PPARalpha activators up-regulate UCP2 expression in hepatocytes through unknown proteins by increased transcription, and neither ROS nor TNFalpha production are the major causes for PPARalpha activators-induced UCP2 up-regulation.