The peroxisome proliferator‐activated receptor α regulates amino acid metabolism

The peroxisome proliferator‐activated receptor α is a ligand‐activated transcription factor that plays an important role in the regulation of lipid homeostasis. PPARα mediates the effects of fibrates, which are potent hypolipidemic drugs, on gene expression. To better understand the biological effects of fibrates and PPARα, we searched for genes regulated by PPARα using oligonucleotide microarray and sub‐tractive hybridization. By comparing liver RNA from wild‐type and PPARα null mice, it was found that PPARα decreases the mRNA expression of enzymes involved in the metabolism of amino acids. Further analysis by Northern blot revealed that PPARα influences the expression of several genes involved in transand deamination of amino acids, and urea synthesis. Direct activation of PPARα using the synthetic PPARα ligand WY14643 decreased mRNA levels of these genes, suggesting that PPARα is directly implicated in the regulation of their expression. Consistent with these data, plasma urea concentrations are modulated by PPARα in vivo. It is concluded that in addition to oxidation of fatty acids, PPARα also regulates metabolism of amino acids in liver, indicating that PPARα is a key controller of intermediary metabolism during fasting.

[1]  T. Saheki,et al.  Long‐chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action , 1996, FEBS letters.

[2]  J. Corton,et al.  Hepatic expression of acute‐phase protein genes during carcinogenesis induced by peroxisome proliferators , 1999, Molecular carcinogenesis.

[3]  S. P. Fodor,et al.  High density synthetic oligonucleotide arrays , 1999, Nature Genetics.

[4]  T. Pineau,et al.  Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators , 1995, Molecular and cellular biology.

[5]  R. Young,et al.  Biomedical Discovery with DNA Arrays , 2000, Cell.

[6]  C. Moncman,et al.  Regulation of mRNA levels for five urea cycle enzymes in rat liver by diet, cyclic AMP, and glucocorticoids. , 1987, Archives of biochemistry and biophysics.

[7]  J. Peters,et al.  Evidence against the peroxisome proliferator-activated receptor alpha (PPARalpha) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription. , 2000, Journal of lipid research.

[8]  W. Wahli,et al.  Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. , 1999, The Journal of clinical investigation.

[9]  D. Kelly,et al.  A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Bertics,et al.  Effect of long-chain fatty acids on triglyceride accumulation, gluconeogenesis, and ureagenesis in bovine hepatocytes. , 1998, Journal of dairy science.

[11]  V. Laudet,et al.  The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates* , 1998, The Journal of Biological Chemistry.

[12]  J. Gustafsson,et al.  Down-regulation of cytochrome P450 2C family members and positive acute-phase response gene expression by peroxisome proliferator chemicals. , 1998, Molecular pharmacology.

[13]  J. Auwerx,et al.  Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[14]  Sander Kersten,et al.  Roles of PPARs in health and disease , 2000, Nature.

[15]  K. Umesono,et al.  A Unified Nomenclature System for the Nuclear Receptor Superfamily , 1999, Cell.

[16]  J. Auwerx,et al.  Alterations in Lipoprotein Metabolism in Peroxisome Proliferator-activated Receptor α-deficient Mice* , 1997, The Journal of Biological Chemistry.

[17]  D. Lavery,et al.  Selective amplification via biotin- and restriction-mediated enrichment (SABRE), a novel selective amplification procedure for detection of differentially expressed mRNAs. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Brosnan,et al.  Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. , 1992, Physiological reviews.

[19]  W. Wahli,et al.  Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting , 1999 .

[20]  T. Pineau,et al.  Peroxisome Proliferator-activated Receptor α Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes* , 1998, The Journal of Biological Chemistry.

[21]  M. Takiguchi,et al.  Hypoglycemia-associated Hyperammonemia Caused by Impaired Expression of Ornithine Cycle Enzyme Genes in C/EBPα Knockout Mice* , 1998, The Journal of Biological Chemistry.

[22]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: nuclear control of metabolism. , 1999, Endocrine reviews.

[23]  J. Bar-Tana,et al.  Mode of Action of Peroxisome Proliferators as Hypolipidemic Drugs. , 1995, The Journal of Biological Chemistry.

[24]  T Hashimoto,et al.  Defect in Peroxisome Proliferator-activated Receptor α-inducible Fatty Acid Oxidation Determines the Severity of Hepatic Steatosis in Response to Fasting* , 2000, The Journal of Biological Chemistry.

[25]  Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. , 1995, The Journal of clinical investigation.

[26]  T. Saheki,et al.  Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood. , 1997, Journal of biochemistry.

[27]  L. Zieve,et al.  Effect of fatty acids on the disposition of ammonia. , 1976, The Journal of pharmacology and experimental therapeutics.

[28]  T. Kooistra,et al.  Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha. , 1999, Blood.

[29]  J. Bar-Tana,et al.  Transcriptional Suppression of the Transferrin Gene by Hypolipidemic Peroxisome Proliferators (*) , 1996, The Journal of Biological Chemistry.

[30]  D. Jump,et al.  Peroxisome proliferator-activated receptor alpha inhibits hepatic S14 gene transcription. Evidence against the peroxisome proliferator-activated receptor alpha as the mediator of polyunsaturated fatty acid regulation of s14 gene transcription. , 1996, The Journal of biological chemistry.

[31]  T. Pineau,et al.  Fenofibrate modifies transaminase gene expression via a peroxisome proliferator activated receptor alpha-dependent pathway. , 1998, Toxicology letters.

[32]  P. J. Snodgrass,et al.  Coordinate induction of the urea cycle enzymes by glucagon and dexamethasone is accomplished by three different mechanisms. , 1993, Archives of biochemistry and biophysics.