Carnitine Transporter OCTN2 and Carnitine Uptake in Bovine Kidney Cells is Regulated by Peroxisome Proliferator-activated Receptor β/δ

Overview

Journal Acta Vet Scand

Publisher Biomed Central

Specialty Veterinary Medicine

Date 2014 Apr 11

PMID 24716857

Citations 4

Authors

Xiaodan Zhou

Robert Ringseis

Gaiping Wen

Klaus Eder

Affiliations

Soon will be listed here.

Abstract

Background: Peroxisome proliferator-activated receptor α (PPARα), a central regulator of fatty acid catabolism, has recently been shown to be a transcriptional regulator of the gene encoding the carnitine transporter novel organic cation transporter 2 (OCTN2) in cattle. Whether PPARβ/δ, another PPAR subtype, which has partially overlapping functions as PPARα and is known to share a large set of common target genes with PPARα, also regulates OCTN2 and carnitine transport in cattle is currently unknown. To close this gap of knowledge, we studied the effect of the PPARβ/δ activator GW0742 on mRNA and protein levels of OCTN2 and carnitine uptake in the presence and absence of the PPARβ/δ antagonist GSK3787 in the bovine Madin-Darby bovine kidney (MDBK) cell line.

Findings: Treatment of MDBK cells with GW0742 caused a strong increase in the mRNA level of the known bovine PPARβ/δ target gene CPT1A in MDBK cells indicating activation of PPARβ/δ. The mRNA and protein level of OCTN2 was clearly elevated in MDBK cells treated with GW0742, but the stimulatory effect of GW0742 on mRNA and protein level of OCTN2 was completely blocked by GSK3787. In addition, GW0742 increased Na⁺-dependent carnitine uptake, which is mediated by OCTN2, into MDBK cells, whereas treatment of cells with the PPARβ/δ antagonist completely abolished the stimulatory effect of GW0742 on carnitine uptake.

Conclusions: The present study shows for the first time that gene expression of the carnitine transporter OCTN2 and carnitine transport are regulated by PPARβ/δ in bovine cells. These novel findings extend the knowledge about the molecular regulation of the OCTN2 gene and carnitine transport in cattle and indicate that regulation of OCTN2 gene expression and carnitine transport is not restricted to the PPARα subtype.

Citing Articles

PGC-1α and MEF2 Regulate the Transcription of the Carnitine Transporter OCTN2 Gene in C2C12 Cells and in Mouse Skeletal Muscle.

Novakova K, Torok M, Panajatovic M, Bouitbir J, Duong F, Handschin C Int J Mol Sci. 2022; 23(20).

PMID: 36293168 PMC: 9604316. DOI: 10.3390/ijms232012304.

The Link Between the Mitochondrial Fatty Acid Oxidation Derangement and Kidney Injury.

Console L, Scalise M, Giangregorio N, Tonazzi A, Barile M, Indiveri C Front Physiol. 2020; 11:794.

PMID: 32733282 PMC: 7363843. DOI: 10.3389/fphys.2020.00794.

SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer.

Juraszek B, Nalecz K Molecules. 2019; 25(1).

PMID: 31861504 PMC: 6982704. DOI: 10.3390/molecules25010014.

Pharmacological doses of niacin stimulate the expression of genes involved in carnitine uptake and biosynthesis and improve the carnitine status of obese Zucker rats.

Couturier A, Ringseis R, Most E, Eder K BMC Pharmacol Toxicol. 2014; 15:37.

PMID: 25012467 PMC: 4094635. DOI: 10.1186/2050-6511-15-37.

References

McGarry J, Brown N . The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997; 244(1):1-14. DOI: 10.1111/j.1432-1033.1997.00001.x. View

Wen G, Ringseis R, Eder K . Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) via a PPRE located in the first intron. Biochem Pharmacol. 2009; 79(5):768-76. DOI: 10.1016/j.bcp.2009.10.002. View

Cheng L, Ding G, Qin Q, Xiao Y, Woods D, Chen Y . Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes. Biochem Biophys Res Commun. 2003; 313(2):277-86. DOI: 10.1016/j.bbrc.2003.11.127. View

Lahjouji K, Elimrani I, Lafond J, Leduc L, Qureshi I, Mitchell G . L-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2. Am J Physiol Cell Physiol. 2004; 287(2):C263-9. DOI: 10.1152/ajpcell.00333.2003. View

Desvergne B, Wahli W . Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999; 20(5):649-88. DOI: 10.1210/edrv.20.5.0380. View

Wen G, Kuhne H, Rauer C, Ringseis R, Eder K . Mouse γ-butyrobetaine dioxygenase is regulated by peroxisome proliferator-activated receptor α through a PPRE located in the proximal promoter. Biochem Pharmacol. 2011; 82(2):175-83. DOI: 10.1016/j.bcp.2011.04.006. View

Zhou X, Wen G, Ringseis R, Eder K . Short communication: the pharmacological peroxisome proliferator-activated receptor α agonist WY-14,643 increases expression of novel organic cation transporter 2 and carnitine uptake in bovine kidney cells. J Dairy Sci. 2013; 97(1):345-9. DOI: 10.3168/jds.2013-7161. View

Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, SHIMANE M . Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem. 1998; 273(32):20378-82. DOI: 10.1074/jbc.273.32.20378. View

Ringseis R, Wen G, Eder K . Regulation of Genes Involved in Carnitine Homeostasis by PPARα across Different Species (Rat, Mouse, Pig, Cattle, Chicken, and Human). PPAR Res. 2012; 2012:868317. PMC: 3486131. DOI: 10.1155/2012/868317. View

10.

Bionaz M, Thering B, Loor J . Fine metabolic regulation in ruminants via nutrient-gene interactions: saturated long-chain fatty acids increase expression of genes involved in lipid metabolism and immune response partly through PPAR-α activation. Br J Nutr. 2011; 107(2):179-91. DOI: 10.1017/S0007114511002777. View

11.

Schlegel G, Keller J, Hirche F, Geissler S, Schwarz F, Ringseis R . Expression of genes involved in hepatic carnitine synthesis and uptake in dairy cows in the transition period and at different stages of lactation. BMC Vet Res. 2012; 8:28. PMC: 3361467. DOI: 10.1186/1746-6148-8-28. View

12.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

13.

Bionaz M, Chen S, Khan M, Loor J . Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation. PPAR Res. 2013; 2013:684159. PMC: 3657398. DOI: 10.1155/2013/684159. View

14.

Shearer B, Wiethe R, Ashe A, Billin A, Way J, Stanley T . Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist. J Med Chem. 2010; 53(4):1857-61. DOI: 10.1021/jm900464j. View

15.

Gutgesell A, Wen G, Konig B, Koch A, Spielmann J, Stangl G . Mouse carnitine-acylcarnitine translocase (CACT) is transcriptionally regulated by PPARalpha and PPARdelta in liver cells. Biochim Biophys Acta. 2009; 1790(10):1206-16. DOI: 10.1016/j.bbagen.2009.06.012. View

16.

Eder K, Ringseis R . The role of peroxisome proliferator-activated receptor alpha in transcriptional regulation of novel organic cation transporters. Eur J Pharmacol. 2009; 628(1-3):1-5. DOI: 10.1016/j.ejphar.2009.11.042. View

17.

Gilde A, van der Lee K, Willemsen P, Chinetti G, van der Leij F, van der Vusse G . Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003; 92(5):518-24. DOI: 10.1161/01.RES.0000060700.55247.7C. View

18.

Wahli W, Devchand P, Ijpenberg A, Desvergne B . Fatty acids, eicosanoids, and hypolipidemic agents regulate gene expression through direct binding to peroxisome proliferator-activated receptors. Adv Exp Med Biol. 1999; 447:199-209. DOI: 10.1007/978-1-4615-4861-4_19. View