Clofibric acid stimulates branched-chain amino acid catabolism by three mechanisms.
Clofibrate promotes catabolism of branched-chain amino acids by increasing the activity of the branched-chain alpha-keto acid dehydrogenase [BCKDH] complex. Depending upon the sex of the rats, nutritional state, and tissue being studied, clofibrate can affect BCKDH complex activity by three different mechanisms. First, by directly inhibiting BCKDH kinase activity, clofibrate can increase the proportion of the BCKDH complex in the active, dephosphorylated state. This occurs in situations in which the BCKDH complex is largely inactive due to phosphorylation, e.g., in the skeletal muscle of chow-fed rats or in the liver of female rats late in the light cycle. Second, by increasing the levels at which the enzyme components of the BCKDH complex are expressed, clofibrate can increase the total enzymatic activity of the BCKDH complex. This is readily demonstrated in livers of rats fed a low-protein diet, a nutritional condition that induces a decrease in the level of expression of the BCKDH complex. Third, by decreasing the amount of BCKDH kinase expressed and therefore its activity, clofibrate induces an increase in the percentage of the BCKDH complex in the active, dephosphorylated state. This occurs in the livers of rats fed a low-protein diet, a nutritional condition that causes inactivation of the BCKDH complex due to upregulation of the amount of BCKDH kinase. WY-14,643, which, like clofibric acid, is a ligand for the peroxisome-proliferator-activated receptor alpha [PPARalpha], does not directly inhibit BCKDH kinase but produces the same long-term effects as clofibrate on expression of the BCKDH complex and its kinase. Thus, clofibrate is unique in its capacity to stimulate BCAA oxidation through inhibition of BCKDH kinase activity, whereas PPARalpha activators in general promote BCAA oxidation by increasing expression of components of the BCKDH complex and decreasing expression of the BCKDH kinase.
Kobayashi
Rumi
R
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Murakami
Taro
T
Obayashi
Mariko
M
Nakai
Naoya
N
Jaskiewicz
Jerzy
J
Fujiwara
Yoko
Y
Shimomura
Yoshiharu
Y
Harris
Robert A
RA
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000284:Administration, Oral; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002995:Clofibric Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007267:Injections; D007658:Ketone Oxidoreductases / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D000597:Amino Acids, Branched-Chain; D004791:Enzyme Inhibitors; D008024:Ligands; D009097:Multienzyme Complexes; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002995:Clofibric Acid; C006253:pirinixic acid; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D011494:Protein Kinases; C035627:(3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase