A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

作者：Ito Minoru; Nagasawa Michiaki; Omae Naoki; Tsunoda Masaki; Ishiyama Junichi; Ide Tomohiro; Akasaka Yunike; Murakami Koji

来源：The Journal of Lipid Research, 2013, 54(6): 1531-1540.

DOI：10.1194/jlr.M031591

• c-Jun N-terminal kinase 2
• cell death-inducing DNA fragmentation factor-alpha-like effector
• microarray
• sterol regulatory element-binding protein-1c
• de novo lipogenesis
• small interfering RNA

Insulin plays important roles in apoptosis and lipid droplet (LD) formation, and it is one of the determinants involved in increasing fat mass. However, the mechanisms underlying insulin-induced enlargement of fat mass remain unclear. Our previous study suggested that insulin-induced increases in LDs are related to c-Jun N-terminal kinase (JNK)2-mediated upregulation of cell death-inducing DNA fragmentation factor-alpha-like effector (CIDE) C in human adipocytes. However, other genes involved in insulin/JNK2-induced LD formation are unknown. Here, we explored insulin/JNK2-regulated genes to clarify the mechanism of enlargement of LDs. Microarray analysis revealed that an insulin/JNK2 pathway mostly regulates expression of genes involved in lipid metabolism, including sterol regulatory element binding protein (SREBP)-1, a key transcription factor of lipogenesis. The JNK inhibitor SP600125 blocked insulin-induced upregulation of SREBP-1c expression. Small interfering RNA-mediated depletion of JNK2 suppressed insulin-induced nuclear accumulation of the active form of SREBP-1 protein and upregulation of SREBP-1c. Furthermore, depletion of JNK2 attenuated insulin-induced upregulation of SREBP-1c target lipogenic enzymes, leading to reduced de novo fatty acid synthesis. In addition, JNK2 coimmunoprecipitated with SREBP-1, reinforcing the correlation between JNK2 and SREBP-1. These results suggest that SREBP-1c is a novel insulin/JNK2-regulated gene and that the JNK2/SREBP-1c pathway mediates insulin-induced fatty acid synthesis, which may lead to enlargement of LDs in human adipocytes.

• 出版日期2013-6