Induction of endogenous genes by peroxisome proliferator activated receptor alpha ligands in a human kidney cell line and in vivo.
The peroxisome proliferator activated receptor alpha (PPARalpha) plays a key role in regulating fatty acid metabolism by regulating expression of genes involved in fatty acid oxidation. To identify endogenous transcripts that could be used as surrogate markers for on-target activity of PPARalpha agonists, we employed a global profiling approach using DNA microarrays. The HK-2 cell line derived from proximal tubules of the human kidney, showed induction of several genes, including pyruvate dehydrogenase kinase 4 (PDK-4) and adipocyte differentiation related protein (ADRP) by PPARalpha ligands. HK-2 cells express detectable levels of PPARalpha and its dimerization partner the retinoid X receptor (RXRalpha) proteins. Induction of PDK-4 in these cells correlates with induction of PDK-4 in the liver of fat-fed hamsters. The magnitude of fibrate induction of PDK-4 in the liver also mirrors the decrease in serum triglyceride levels. Thus, induction of PDK-4 by PPARalpha agonists in the HK-2 cell model closely correlates with its induction in vivo and may represent an early marker for PPARalpha agonist action.
Liu
Phillip C C
PC
Department of Biotechnology, Experimental Station, Bristol-Myers Squibb Company, Wilmington, DE 19880, USA.
Huber
Reid
R
Stow
Mark D
MD
Schlingmann
Karen L
KL
Collier
Paul
P
Liao
Boshan
B
Link
John
J
Burn
Tim C
TC
Hollis
Greg
G
Young
Peter R
PR
Mukherjee
Ranjan
R
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008099:Liver / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008647:Mesocricetus; D020411:Oligonucleotide Array Sequence Analysis; D000070780:Perilipin-2; D010671:Phenylurea Compounds / Q000494:pharmacology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014280:Triglycerides / Q000097:blood
D002087:Butyrates; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; C121804:GW 9578; D011345:Fenofibrate