Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner.
Regulation of gene expression of three putative long-chain fatty acid transport proteins, fatty acid translocase (FAT), mitochondrial aspartate aminotransferase (mAspAT), and fatty acid transport protein (FATP), by drugs that activate peroxisome proliferator-activated receptor (PPAR) alpha and gamma were studied using normal and obese mice and rat hepatoma cells. FAT mRNA was induced in liver and intestine of normal mice and in hepatoma cells to various extents only by PPARalpha-activating drugs. FATP mRNA was similarly induced in liver, but to a lesser extent in intestine. The induction time course in the liver was slower for FAT and FATP mRNA than that of an mRNA encoding a peroxisomal enzyme. An obligatory role of PPARalpha in hepatic FAT and FATP induction was demonstrated, since an increase in these mRNAs was not observed in PPARalpha-null mice. Levels of mAspAT mRNA were higher in liver and intestine of mice treated with peroxisome proliferators, while levels in hepatoma cells were similar regardless of treatment. In white adipose tissue of KKAy obese mice, thiazolidinedione PPARgamma activators (pioglitazone and troglitazone) induced FAT and FATP more efficiently than the PPARalpha activator, clofibrate. This effect was absent in brown adipose tissue. Under the same conditions, levels of mAspAT mRNA did not change significantly in these tissues. In conclusion, tissue-specific expression of FAT and FATP genes involves both PPARalpha and -gamma. Our data suggest that among the three putative long-chain fatty acid transporters, FAT and FATP appear to have physiological roles. Thus, peroxisome proliferators not only influence the metabolism of intracellular fatty acids but also cellular uptake, which is likely to be an important regulatory step in lipid homeostasis.
Motojima
K
K
Department of Biochemistry, School of Pharmaceutical Sciences, Toho University, Funabashi, Chiba 274, Japan. motojima@phar.toho-u.ac.jp
Passilly
P
P
Peters
J M
JM
Gonzalez
F J
FJ
Latruffe
N
N
D000272:Adipates / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens; D002994:Clofibrate / Q000494:pharmacology; D017931:DNA Primers; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000272:Adipates; D018955:CD36 Antigens; D017931:DNA Primers; D008562:Membrane Glycoproteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C013966:dioctyl adipate; C006253:pirinixic acid; D004051:Diethylhexyl Phthalate; D002994:Clofibrate