Activation of SIK2 inhibits gluconeogenesis and alleviates lipogenesis-induced inflammatory response by SIK2-CRTC2-ACC1 in hepatocytes of large yellow croaker (Larimichthys crocea)

Abstract

As an important kinase that maintains metabolic homeostasis, salt-induced kinase 2 (SIK2) inhibits adipogenesis in adipocytes and regulates mammalian glucose metabolism. Excessive lipid accumulation can lead to an inflammatory response, and SIK2 also controls the expression of inflammatory cytokines. However, the precise mechanisms and interconnections through which SIK2 modulates these processes remain incompletely understood. The present study explores the regulatory role of SIK2 in hepatic glucose and lipid metabolism and lipogenesis-induced inflammatory response of Larimichthys crocea. We found that palmitic acid or glucose reduces sik2 mRNA expression, while its expression increases in response to insulin. Further, SIK2 reduces glucose content by inhibiting gluconeogenesis and activating insulin signaling pathways. Meanwhile, SIK2 overexpression decreases lipogenesis-related gene expression and increases lipolysis-related gene expression, alleviating hepatocyte lipid accumulation. Due to sequence conservation, SIK2 mutants are constructed. Only the T176A mutant weakens the inhibition of wt-SIK2 on the acetyl-CoA carboxylase 1 (ACC1) promoter through cyclic AMP-responsive element-binding protein (CREB). It increases the expression of CREB-regulated transcription coactivator 2 (CRTC2) in the nucleus. Then, ACC1 inhibition attenuates the inflammatory response. SIK2 alleviates the inflammatory response by reducing pro-inflammatory cytokines expression and inactivating the mitogen-activated protein kinase (MAPK) pathway. Furthermore, similar results were obtained by inhibiting SIK2 in vivo. Overall, this study explores the role of SIK2 in hepatic glucose and lipid metabolism and lipogenesis-induced inflammatory response in fish for the first time, which provides insights into the functional protection of SIK2 in vertebrate evolution and may serve as a target for the treatment of nutritional and immune disorders.