title: Induction of endogenous genes by peroxisome proliferator activated receptor alpha ligands in a human kidney cell line and in vivo.
abstract: 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.
authors.affiliation: Department of Biotechnology, Experimental Station, Bristol-Myers Squibb Company, Wilmington, DE 19880, USA.
authors.forename: Phillip C C
authors.initials: PC
authors.lastname: Liu
authors.forename: Reid
authors.initials: R
authors.lastname: Huber
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stow
authors.forename: Karen L
authors.initials: KL
authors.lastname: Schlingmann
authors.forename: Paul
authors.initials: P
authors.lastname: Collier
authors.forename: Boshan
authors.initials: B
authors.lastname: Liao
authors.forename: John
authors.initials: J
authors.lastname: Link
authors.forename: Tim C
authors.initials: TC
authors.lastname: Burn
authors.forename: Greg
authors.initials: G
authors.lastname: Hollis
authors.forename: Peter R
authors.initials: PR
authors.lastname: Young
authors.forename: Ranjan
authors.initials: R
authors.lastname: Mukherjee
mesh_terms: 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
chemical_list: 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