골격근에서 지방 대사에 대한 SENP2의 역할

Abstract

SUMO modification (SUMOylation) is a posttranslational modification of protein, which is a reversible process. SUMOylation of proteins has many functions. Many papers reported protein stability, transcriptional regulation, and nuclear-cytosolic transport by SUMOylation. Typically, small fraction of protein is SUMOylated and this modification is rapidly reversed by the action of deSUMOylating enzymes. deSUMOylation is catalyzed by SUMO-specific proteases (SENPs). However, the physiological function of SENPs in energy metabolism remains unclear. In this study, I investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and SENP2 skeletal muscle specific transgenic mouse models. When C2C12 myotubes were treated with palmitate, expression of SENP2 was increased via TLR4-Myd88-NF-κB signaling pathway. This increase promoted the recruitment of PPAR and PPAR, through deSUMOylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 induced by palmitate increased levels of fatty acid oxidation in C2C12 myotubes. When PPAR, PPAR or SENP2 were silenced, palmitate does not increase fatty acid oxidation and expressions of fatty acid oxidation associated genes. When C2C12 myotubes were transfected with SENP2 adeno viruses, fatty acid oxidation levels were increased. Expression levels of fatty acid oxidation associated genes, such as CPT1b and ACSL1, were increased by SENP2 in C2C12 myotubes. SENP2 skeletal muscle specific transgenic FVB (SENP2 TG) mice showed significant improvement of glucose tolerance, insulin resistance, body weight and fat mass in a high fat diet condition. Also, β-oxidation and mitochondrial mass are increased in mouse skeletal muscle tissue of SENP2 TG mice. Furthermore, Insulin signaling pathway-related genes were up-regulated by SENP2 overexpression in skeletal muscle tissue. In summary, these results indicate that SENP2 plays an important role in fatty acid metabolism and mitochondrial biogenesis in skeletal muscle. Furthermore, SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders.