PGC-1α Coactivates PDK4 Gene Expression via the Orphan Nuclear Receptor ERRα: a Mechanism for Transcriptional Control of Muscle Glucose Metabolism

Abstract

The transcriptional coactivator PGC-1␣ is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1␣ expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1␣ in C 2 C 12 myotubes induced PDK4 mRNA and protein expression. PGC-1␣-mediated activation of PDK4 expression was shown to occur at the transcriptional level and was mapped to a putative nuclear receptor binding site. Gel shift assays demonstrated that the PGC-1␣-responsive element bound the estrogen-related receptor ␣ (ERR␣), a recently identified component of the PGC-1␣ signaling pathway. In addition, PGC-1␣ was shown to activate ERR␣ expression. Chromatin immunoprecipitation assays confirmed that PGC-1␣ and ERR␣ occupied the mPDK4 promoter in C 2 C 12 myotubes. Additionally, transfection studies using ERR␣-null primary fibroblasts demonstrated that ERR␣ is required for PGC-1␣-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1␣ on PDK4 gene transcription, overexpression of PGC-1␣ in C 2 C 12 myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1␣/ERR␣ target and suggest a mechanism whereby PGC-1␣ exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.

Characterization of the porcine differentially expressed PDK4 gene and association with meat quality

“…These indicated that the PDK4 may play an important role in the skeletal muscle. It was reported that PDK4 was activated by PGC-1a via the ERRa [17,18] and skeletal-musclespecific overexpression of PGC-1a could result in a fiber type switch from fast-twitch (type II) to slow-twitch (type I) oxidative fibers [19]. These suggested that the PDK4 activated by PGC-1a may be one of the reasons that Meishan had more slow-twitch oxidative fibers than Yorkshire.…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…(2007) and drives the transcription of genes involved in fatty acid metabolism (such as CD36, CPT1, MCAD) in order to cope with excess provision of lipids from the circulation, and of PDK4 (Wende et al. 2005), which further suppresses glucose oxidation by decreasing PDH activity (Wu et al. 1998).…”

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…Cumulative evidences indicate that another ERR subtype, ERRa, plays significant roles in energy metabolism and mitochondrial biogenesis in certain target cells and tissues via direct regulation of genes involved in fatty acid oxidation, ERRb suppresses prostate cancer cell growth S Yu et al glucose metabolism, oxidative phosphorylation and mitochondrial fusion Huss et al, 2004;Schreiber et al, 2004;Wende et al, 2005;Soriano et al, 2006;Villena et al, 2007). Moreover, ectopic ERRa expression can promote lipid accumulation in primary cardiac myocytes (Huss et al, 2004), whereas its loss of function reduces body fat in ERRa-knockout mouse (Luo et al, 2003).…”