Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids.
The activity of the pyruvate dehydrogenase complex (PDC) is regulated by covalent modification of its E1 component, which is catalyzed by specific pyruvate dehydrogenase kinases (PDKs) and phosphatases. In the liver, PDK2 and PDK4 are the most abundant PDK isoforms, which are responsible for inactivation of PDC when glucose availability is scarce in the body. In the present study, regulatory mechanisms of hepatic PDC were examined before and after the onset of type 2 diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using Long-Evans Tokushima Otsuka (LETO) rats as controls. Plasma glucose and insulin concentrations were at normal levels in rats aged 8 weeks, but were significantly higher in OLETF than in LETO rats aged 25 weeks, indicating insulin resistance in OLETF rats. Plasma free fatty acids (FFAs) were 1.6-fold concentrated, and the liver PDC activity was significantly lower in OLETF than in LETO rats at both ages, suggesting suppression of pyruvate oxidative decarboxylation in OLETF rats before and after the onset of diabetes. Pyruvate dehydrogenase kinase activity and abundance of PDK2 and PDK4 proteins, as well as mRNAs, were greater in OLETF rats at both ages. These results suggest that persistently elevated levels of circulating free fatty acid in normal and diabetic OLETF rats play an important role in stimulating PDK2 and PDK4 expression in liver.
Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601, Japan.
Gustavo
G
Bajotto
Taro
T
Murakami
Masaru
M
Nagasaki
Bolin
B
Qin
Yoshiyuki
Y
Matsuo
Ken
K
Maeda
Masayo
M
Ohashi
Yoshiharu
Y
Oshida
Yuzo
Y
Sato
Yoshiharu
Y
Shimomura
D000367:Age Factors; D000818:Animals; D003924:Diabetes Mellitus, Type 2; D005227:Fatty Acids / Q000097:blood / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020334:Rats, Inbred OLETF; D015854:Up-Regulation / Q000187:drug effects
D005227:Fatty Acids; C000631436:Pdk2 protein, rat; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D017346:Protein Serine-Threonine Kinases