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.
MeSH terms
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Animals
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Butyrates / pharmacology
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Cells, Cultured
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Cricetinae
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Enzyme Activation
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Fatty Acids / metabolism*
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Fenofibrate / pharmacology
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Gene Expression Regulation / physiology
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Humans
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Hypolipidemic Agents / pharmacology
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Isoenzymes / biosynthesis*
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Kidney Tubules, Proximal / enzymology
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Kidney Tubules, Proximal / metabolism
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Kidney Tubules, Proximal / physiology*
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Ligands
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Liver / enzymology
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Male
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Mesocricetus
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Oligonucleotide Array Sequence Analysis
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Perilipin-2
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Phenylurea Compounds / pharmacology
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Protein Kinases / biosynthesis*
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Protein Kinases / genetics
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Protein Kinases / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Retinoid X Receptors
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / agonists*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology
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Triglycerides / blood
Substances
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Butyrates
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Fatty Acids
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Hypolipidemic Agents
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Isoenzymes
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Ligands
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Membrane Proteins
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PLIN2 protein, human
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Perilipin-2
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Phenylurea Compounds
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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Triglycerides
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Protein Kinases
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pyruvate dehydrogenase kinase 4
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GW 9578
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Fenofibrate