Essential role of the PGC-1α/PPARβ axis in Ucp3 gene induction.

Key Points: We report that the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-α (PGC-1α)/PPARβ axis is a crucial mediator of uncoupling protein 3 (UCP3) expression in skeletal muscle cells via the transactivativation of a distal PPAR response element at the Ucp3 gene promoter. This mechanism is activated during the myogenic process and by high concentrations of fatty acids independent of PGC-1α protein levels. Ucp3 is essential for PGC-1α-induced oxidative capacity and the adaptive mitochondrial response to fatty acid exposure. These findings provide further evidence for the broad spectrum of the coactivator action in mitochondrial homeostasis, positioning the PGC-1ɑ/PPARβ axis as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.

Abstract: Uncoupling protein 3 (UCP3) has an essential role in fatty acid metabolism and mitochondrial redox regulation in skeletal muscle. However, the molecular mechanisms involved in the expression of Ucp3 are poorly known. In the present study, we show that the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1-α (PGC-1α)/PPARβ axis is a crucial mediator of Ucp3 expression in skeletal muscle cells. In silico analysis of the UCP3 promoter and quantitative chromatin immunoprecipitation experiments revealed that the induction of the UCP3 transcript is mediated by the transactivation of a distal PPAR response element at the Ucp3 gene promoter by the coactivator PGC-1α. This mechanism is activated during myogenesis and during metabolic stress induced by fatty acids independent of PGC-1α protein levels. We also provide evidence that Ucp3 is essential for PGC-1α-induced oxidative capacity. Taken together, our results highlight PGC-1ɑ/PPARβ as an essential component of the molecular regulation of Ucp3 gene in skeletal muscle cells.