Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

作者：Zhang Wenliang; Mottillo Emilio P; Zhao Jiawei; Gartung Allison; VanHecke Garrett C; Lee Jen Fu; Maddipati Krishna R; Xu Haiyan; Ahn Young Hoon; Proia Richard L; Granneman James G^*; Lee Menq Jer

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(46): 32178-32185.

DOI：10.1074/jbc.M114.601096

• Adipose Tissue
• AP1 Transcription Factor (AP-1)
• c-Jun N-terminal Kinase (JNK)
• Inflammation
• Interleukin 6 (IL-6)
• Lipolysis
• Beta 3 Adrenergic Receptor
• Hormone-sensitive Lipase
• Sphingosine Kinase

Adipocyte lipolysis can increase the production of inflammatory cytokines such as interleukin-6 (IL-6) that promote insulin resistance. However, the mechanisms that link lipolysis with inflammation remain elusive. Acute activation of (3)-adrenergic receptors (ADRB3) triggers lipolysis and up-regulates production of IL-6 in adipocytes, and both of these effects are blocked by pharmacological inhibition of hormone-sensitive lipase. We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases sphingosine 1-phosphate production in adipocytes in a manner that also depends on hormone-sensitive lipase activity. Mechanistically, we found that adipose lipolysis-induced SphK1 up-regulation is mediated by the c-Jun N-terminal kinase (JNK)/activating protein-1 signaling pathway. Inhibition of SphK1 by sphingosine kinase inhibitor 2 diminished the ADRB3-induced IL-6 production both in vitro and in vivo. Induction of IL-6 by ADRB3 activation was suppressed by siRNA knockdown of Sphk1 in cultured adipocytes and was severely attenuated in Sphk1 null mice. Conversely, ectopic expression of SphK1 increased IL-6 expression in adipocytes. Collectively, these data demonstrate that SphK1 is a critical mediator in lipolysis-triggered inflammation in adipocytes.

• 出版日期2014-11-14