Regulation of Octn2 transporter (SLC22A5) by peroxisome proliferator activated receptor alpha.
The tissue distribution and disposition of carnitine, which plays an important role in the transport of long-chain fatty acids across the mitochondrial inner membrane for beta-oxidation, are well controlled by carnitine transporter organic cation/carnitine transporter 2 (OCTN2). Since little information is available on regulation of the expression of the OCTN2 gene, we examined the factors that affect the expression level of rat Octn2 (rOctn2), focusing on nuclear receptor peroxisome proliferator activated receptor alpha (PPARalpha), which regulates expression of genes associated with beta-oxidation of fatty acids. mRNA of rOctn2 was induced by the PPARalpha ligand fenofibrate in primary-cultured rat hepatocytes. Further, the PPARalpha ligand Wy14643 increased the expression of Octn2 in wild-type mice, but not in PPARalpha knockout mice. Analysis of the rOctn2 promoter region suggested the presence of putative cis elements of PPARalpha. Wistar rats treated with intraperitoneal fenofibrate administration showed increased expression of rOctn2 mRNA in liver, and uptake of [3H]carnitine by freshly isolated hepatocytes derived from those rats was also increased. In conclusion, our results indicate that the nuclear receptor PPARalpha directly up-regulates the expression of rOctn2 and increases the hepatic uptake of carnitine via rOctn2.
Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Tomoji
T
Maeda
Takeru
T
Wakasawa
Miho
M
Funabashi
Akimasa
A
Fukushi
Masaharu
M
Fujita
Kiyoto
K
Motojima
Ikumi
I
Tamai
D000818:Animals; D015152:Blotting, Northern; D002331:Carnitine / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D011345:Fenofibrate / Q000494:pharmacology; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074058:Solute Carrier Family 22 Member 5; D014162:Transfection
D000960:Hypolipidemic Agents; D027701:Organic Cation Transport Proteins; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D008156:Luciferases; D002331:Carnitine; D011345:Fenofibrate