PMID- 12435272
OWN - NLM
STAT- MEDLINE
DCOM- 20030318
LR  - 20211203
IS  - 0264-6021 (Print)
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 369
IP  - Pt 3
DP  - 2003 Feb 1
TI  - Investigation of potential mechanisms regulating protein expression of hepatic 
      pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid 
      hormone.
PG  - 687-95
AB  - 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.
FAU - Holness, Mark J
AU  - Holness MJ
AD  - 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.
FAU - Bulmer, Karen
AU  - Bulmer K
FAU - Smith, Nicholas D
AU  - Smith ND
FAU - Sugden, Mary C
AU  - Sugden MC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Fatty Acids)
RN  - 0 (Isoenzymes)
RN  - 0 (Lipids)
RN  - 0 (Pdk2 protein, rat)
RN  - 0 (Pdk4 protein, rat)
RN  - 0 (Peroxisome Proliferators)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Thyroid Hormones)
RN  - 0 (Transcription Factors)
RN  - 86C4MRT55A (pirinixic acid)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (pyruvate dehydrogenase kinase 4)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/metabolism
MH  - Disease Models, Animal
MH  - Fatty Acids/*metabolism/pharmacology
MH  - Female
MH  - Hyperthyroidism/*metabolism
MH  - Isoenzymes/metabolism
MH  - Lipid Metabolism
MH  - Lipids/pharmacology
MH  - Liver/drug effects/*enzymology
MH  - Mitochondria, Liver/metabolism
MH  - Oxidation-Reduction
MH  - Peroxisome Proliferators/pharmacology
MH  - Protein Kinases/*metabolism
MH  - Protein Serine-Threonine Kinases
MH  - Pyrimidines/pharmacology
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Cytoplasmic and Nuclear/drug effects/metabolism
MH  - Receptors, Retinoic Acid/metabolism
MH  - Retinoid X Receptors
MH  - Signal Transduction
MH  - Starvation
MH  - Thyroid Hormones/*metabolism/pharmacology
MH  - Transcription Factors/drug effects/metabolism
PMC - PMC1223128
EDAT- 2002/11/19 04:00
MHDA- 2003/03/19 04:00
PMCR- 2003/08/01
CRDT- 2002/11/19 04:00
PHST- 2002/11/18 00:00 [accepted]
PHST- 2002/11/07 00:00 [revised]
PHST- 2002/09/27 00:00 [received]
PHST- 2002/11/19 04:00 [pubmed]
PHST- 2003/03/19 04:00 [medline]
PHST- 2002/11/19 04:00 [entrez]
PHST- 2003/08/01 00:00 [pmc-release]
AID - BJ20021509 [pii]
AID - 10.1042/BJ20021509 [doi]
PST - ppublish
SO  - Biochem J. 2003 Feb 1;369(Pt 3):687-95. doi: 10.1042/BJ20021509.