Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-alpha and -gamma.
The transport and metabolism of organic cationic endobiotics, nutrients, and drugs are essential hepatic functions. Slc22A1 is the basolateral liver transporter mediating the uptake of organic cations; however, little is known about the regulation of this transport protein. Peroxisome proliferator agonist receptor (PPAR)-alpha and -gamma agonists are commonly used agents that regulate many hepatocellular transport functions. Thus the purpose of this study was to examine the effects of PPAR agonists on the hepatic regulation and function of Slc22a1. Mice and H35 cells were administered PPAR-alpha and -gamma agonists, and the effect on Slc22a1 gene expression was measured. We subsequently cloned the Slc22a1 promoter and employed chimeric constructs to assay Slc22a1 gene transcription. The effects of PPAR-agonist treatment on organic cation uptake was also assayed. Slc22a1 expression was increased by PPAR-alpha and -gamma agonist treatment in both murine livers and H35 cells. Gene expression in H35 cells was further increased following transfection with expression vectors of PPAR transcription factors and PPAR agonist treatment. We cloned the promoter region of Slc22a1 and identified a PPAR-response element, and transfections with chimeric Slc22a1; promoter-reporter gene constructs demonstrate that the increased gene expression was transcriptionally regulated. Functional assays confirmed that cells treated with PPAR agonists displayed significant increases in organic cation uptake. PPAR-alpha and -gamma agonists transcriptionally increase Slc22a1 gene expression, and the increased Slc22a1 expression results in enhanced cellular organic cation uptake. These studies may have implication for the uptake of organic cationic drugs and for lipid metabolism.
Nie
Wenxian
W
Department of Medicine, Division of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sweetser
Seth
S
Rinella
Mary
M
Green
Richard M
RM
D000818:Animals; D050482:Catecholamine Plasma Membrane Transport Proteins; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D050482:Catecholamine Plasma Membrane Transport Proteins; D027682:Cation Transport Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D020025:Peroxisome Proliferators; C103766:Slc22a1 protein, mouse