Pyruvate dehydrogenase kinase 4 mRNA is increased in the hypertrophied ventricles of carnitine‐deficient juvenile visceral steatosis (JVS) mice

Abstract

We isolated a mouse homologue cDNA of pyruvate dehydrogenase (PDH) kinase 4 (PDK4) with differential mRNA display as an up-regulated gene in the hypertrophied ventricles of juvenile visceral steatosis (JVS) mice with systemic carnitine deficiency. The PDK4 mRNA level was 5 times higher in JVS mice than in control mice under fed conditions. After 24 h starvation, this level increased to 20 times in JVS and 7 times in control, compared with the control fed level. On the other hand, carnitine administration reduced the high level of PDK4 mRNA in JVS mice to the control fed level. In control mice, the change in PDK4 mRNA was inversely correlated with the change in PDH activity. In JVS mice, however, the PDK4 mRNA level was not always correlated with the active-form PDH level.

Regulation of Pyruvate Dehydrogenase Kinase Expression by Peroxisome Proliferator–Activated Receptor-α Ligands, Glucocorticoids, and Insulin

“…Fatty acids function as endogenous PPAR-␣ ligands (17), and plasma FFAs are elevated in conditions thus far identified to increase PDK4 expression. These include starvation (9 -12), diabetes (9,10), high-fat-diet feeding (32), hibernation (33), carnitine deficiency (34), and exercise (35). WY-14,643 induces PDK4 expression in skeletal muscle (10), kidney (36), heart (36), and liver (this study) of normal mice, but not in tissues of PPAR-␣-null mice (36).…”

Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids

“…Our data might offer an explanation for the remarkable finding that, in heart, PDK4 is very often one of the genes that displays the largest changes in expression levels in response to metabolic disease or conditions that affect hepatic or cardiac metabolism. For example, PDK4 was elevated in animal models for physiological and pathological cardiac hypertrophy [41], diabetic cardiomyopathy [42,43] and FAO defects [44,45]. To summarize, AMPK and fatty acids synergistically induce PDK4 expression and decrease cellular glucose oxidation.…”

Adaptive Increase in Pyruvate Dehydrogenase Kinase 4 during Starvation Is Mediated by Peroxisome Proliferator-Activated Receptor α

“…Since naturally occurring fatty acids are potent PPAR␣ agonists (38), activation of this receptor by free fatty acids may be a major part of the mechanism responsible for increased PDK4 expression in tissues during starvation (10 -13), diabetes (10,11), hiberna- tion (17), and carnitine deficiency (18). The lack of complete blockage of PDK4 expression at the protein level in the heart of PPAR␣ null mice indicates that additional mechanisms that contribute to regulation of PDK4 expression during starvation.…”

“…Recent studies have documented increased PDK4 expression in various tissues as a consequence of starvation (10 -13), high-fat diet feeding (14) (P. Wu and R. A. Harris, unpublished data), diabetes (10,11), hibernation (17), carnitine deficiency (18), and exercise (19). Elevated plasma level of fatty acids is a shared characteristic of these conditions, making a role for fatty acids in upregulation of PDK4 gene expression attractive as a working hypothesis, particularly since fatty acids are already known to regulate expression of a number of important metabolic enzymes (20 -22).…”