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.
Nakatani
Teruyo
T
Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan.
Tsuboyama-Kasaoka
Nobuyo
N
Takahashi
Mayumi
M
Miura
Shinji
S
Ezaki
Osamu
O
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D005395:Fish Oils / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D007473:Ion Channels; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D011506:Proteins / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
D005395:Fish Oils; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C006253:pirinixic acid; D011345:Fenofibrate