Treatment with pharmacological peroxisome proliferator-activated receptor alpha agonist clofibrate causes upregulation of organic cation transporter 2 in liver and small intestine of rats.
Activation of PPARalpha by clofibrate has recently been shown to cause upregulation of carnitine transporter organic cation transporter (OCTN) 2 and elevated carnitine concentrations in rat liver. The present study has been conducted to further explore the effect of clofibrate on OCTN expression, carnitine biosynthesis, and carnitine accumulation in different rat tissues, and thus two groups of rats were fed diets containing 0.5% clofibrate or 0% clofibrate (control group). PPARalpha-responsive genes were markedly upregulated in the liver (P<0.05), moderately in small intestine, but only slightly in other extrahepatic tissues by clofibrate. Relative mRNA concentration of OCTN2 in liver and small intestine was increased in rats fed clofibrate (P<0.05), whereas in other extrahepatic tissues mRNA concentration of OCTN2 did not differ between treatment groups. Concentration of total carnitine was higher in liver and small intestine but lower in plasma, kidney, and brain of rats fed clofibrate (P<0.05). Moreover, concentration of the carnitine precursor trimethyllysine and mRNA concentrations of specific genes involved in carnitine biosynthesis were increased in livers of rats fed clofibrate (P<0.05). The present study shows that clofibrate causes not only upregulation of OCTN2 in the liver but also in small intestine, and thus suggests that an increased intestinal absorption of carnitine might also contribute to the clofibrate-induced increase in hepatic carnitine concentration. Furthermore, the present results also indicate that an increased carnitine biosynthesis also contributes to the clofibrate-induced increase in hepatic carnitine concentration.
Ringseis
Robert
R
Institut für Agrar- und Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Emil-Abderhalden-Strasse 26, D-06108 Halle(Saale), Germany. robert.ringseis@landw.uni-halle.de
Pösel
Stefanie
S
Hirche
Frank
F
Eder
Klaus
K
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000446:Aldehyde-Lyases / Q000378:metabolism; D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D002331:Carnitine / Q000097:blood / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074058:Solute Carrier Family 22 Member 5; D015854:Up-Regulation; D050563:gamma-Butyrobetaine Dioxygenase / Q000378:metabolism
D000960:Hypolipidemic Agents; D027701:Organic Cation Transport Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D001622:Betaine; C003712:trimethyllysine; C002889:gamma-butyrobetaine; D050563:gamma-Butyrobetaine Dioxygenase; D042926:Cytochrome P-450 CYP4A; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase; D000446:Aldehyde-Lyases; D002994:Clofibrate; D008239:Lysine; D002331:Carnitine