Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone.
Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-alpha (PPARalpha). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-alpha. Heterodimerization partners for retinoid X receptors (RXRs) include PPARalpha and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-alpha activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARalpha activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARalpha, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARalpha or TR with the RXR receptor and that effects of PPARalpha activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.
Holness
Mark J
MJ
Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
Bulmer
Karen
K
Smith
Nicholas D
ND
Sugden
Mary C
MC
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006980:Hyperthyroidism / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction; D013217:Starvation; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
D005227:Fatty Acids; D007527:Isoenzymes; D008055:Lipids; C000631436:Pdk2 protein, rat; C000631440:Pdk4 protein, rat; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013963:Thyroid Hormones; D014157:Transcription Factors; C006253:pirinixic acid; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D017346:Protein Serine-Threonine Kinases