Regulation of Octn2 Transporter (SLC22A5) by Peroxisome Proliferator Activated Receptor Alpha

Abstract

The tissue distribution and disposition of carnitine, which plays an important role in the transport of longchain fatty acids across the mitochondrial inner membrane for b b-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 (PPARa a), which regulates expression of genes associated with b b-oxidation of fatty acids. mRNA of rOctn2 was induced by the PPARa a ligand fenofibrate in primary-cultured rat hepatocytes. Further, the PPARa a ligand Wy14643 increased the expression of Octn2 in wild-type mice, but not in PPARa a knockout mice. Analysis of the rOctn2 promoter region suggested the presence of putative cis elements of PPARa a. Wistar rats treated with intraperitoneal fenofibrate administration showed increased expression of rOctn2 mRNA in liver, and uptake of [ 3 H]carnitine by freshly isolated hepatocytes derived from those rats was also increased. In conclusion, our results indicate that the nuclear receptor PPARa a directly up-regulates the expression of rOctn2 and increases the hepatic uptake of carnitine via rOctn2.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Treatment of mice with PPAR␣ agonists increase hepatic and intestinal Octn2 mRNA expression and carnitine levels in wild-type mice but not in PPAR␣-null mice (Fig. 22) (Ringseis et al, 2007;Maeda et al, 2008). Clofibrate up-regulates Octn1 (liver) and Octn2 mRNA (liver, duodenum, jejunum) in mice ( Fig.…”

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

“…Activation of PPAR alpha is associated with an increase mRNA expression of OCTN2 in liver, skeletal muscle, gut and kidney from pigs (Ringseis et al, 2008), rats (Maeda et al, 2008; A C C E P T E D M A N U S C R I P T…”

Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

“…19) Establishment of OAT2-Expressing HEK293 Cell Line HEK293 cells were transfected with pcDNA3.1 plasmid DNA alone or containing OAT2 cDNA (pcDNA3.1/OAT2) using Lipofectamine 2000 (Invitrogen) as described previously. 21) Stable transfectants were selected in the presence of 1 mg/ml G418 (Sigma-Aldrich) for about 2 weeks; the established cell lines were designated as HEK293/OAT2 and HEK293/pcDNA3.1, respectively. These cells were routinely grown in Dulbecco's modified Eagle medium supplemented with 10% FBS, 100 units/ml penicillin, 100 mg/ml streptomycin, and 400 mg/ml G418 in a humidified incubator at 37°C in an atmosphere of 5% CO 2 in air.…”