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
Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, Michigan 48202.
J Biol Chem. 2014 Nov 14;289(46):32178-32185. doi: 10.1074/jbc.M114.601096. Epub 2014 Sep 24.
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 β3-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.
脂肪细胞的脂解作用可增加白细胞介素-6（IL-6）等促炎细胞因子的产生，这些细胞因子会促进胰岛素抵抗。然而，将脂解作用与炎症联系起来的机制仍不清楚。β3-肾上腺素能受体（ADRB3）的急性激活会触发脂解作用，并上调脂肪细胞中IL-6的产生，而这两种效应都可被激素敏感性脂肪酶的药理学抑制所阻断。我们报告称，刺激ADRB3会诱导鞘氨醇激酶1（SphK1）的表达，并以一种同样依赖于激素敏感性脂肪酶活性的方式增加脂肪细胞中鞘氨醇-1-磷酸的产生。从机制上来说，我们发现脂肪脂解诱导的SphK1上调是由c-Jun氨基末端激酶（JNK）/激活蛋白-1信号通路介导的。鞘氨醇激酶抑制剂2对SphK1的抑制在体外和体内均减少了ADRB3诱导的IL-6产生。在培养的脂肪细胞中，通过小干扰RNA敲低Sphk1可抑制ADRB3激活诱导的IL-6产生，而在Sphk1基因敲除小鼠中这种诱导作用则严重减弱。相反，SphK1的异位表达增加了脂肪细胞中IL-6的表达。总的来说，这些数据表明SphK1是脂肪细胞中脂解触发炎症的关键介质。
