Pierre Nicolas, Fernández-Verdejo Rodrigo, Regnier Pauline, Vanmechelen Simon, Demeulder Bénédicte, Francaux Marc
Institute of Neuroscience, Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
Cell Biol Int. 2016 Jan;40(1):91-9. doi: 10.1002/cbin.10542. Epub 2015 Sep 17.
Endoplasmic reticulum (ER) stress is a central actor in the physiopathology of insulin resistance (IR) in various tissues. The subsequent unfolded protein response (UPR) interacts with insulin signaling through inositol-requiring 1α (IRE1α) activation and tribbles homolog 3 (TRB3) expressions. IRE1α impairs insulin actions through the activation of c-Jun N-terminal kinase (JNK), and TRB3 is a pseudokinase inhibiting Akt. In muscle cells, the link between ER stress and IR has only been demonstrated by using chemical ER stress inducers or overexpression techniques. However, the involvement of ER stress in lipid-induced muscle IR remains controversial. The aim of the study is to test whether palmitate-induced IRE1α signaling and TRB3 expression disturb insulin signaling in myogenic cells. C2C12 myotubes were exposed to palmitate and then stimulated with insulin. siRNA transfection was used to downregulate TRB3 and IRE1α. Palmitate increased TRB3 expression, activated IRE1α signaling, and reduced the insulin-dependent Akt phosphorylation. Knocking down TRB3 or IRE1α did not prevent the inhibitory effect of palmitate on Akt phosphorylation. Our results support the idea that ER stress is not responsible for lipid-induced IR in C2C12 myotubes.
内质网（ER）应激是多种组织中胰岛素抵抗（IR）病理生理学的关键因素。随后的未折叠蛋白反应（UPR）通过肌醇需求酶1α（IRE1α）激活和TRIB3同源物3（TRB3）表达与胰岛素信号相互作用。IRE1α通过激活c-Jun氨基末端激酶（JNK）损害胰岛素作用，而TRB3是一种抑制Akt的假激酶。在肌肉细胞中，ER应激与IR之间的联系仅通过使用化学ER应激诱导剂或过表达技术得以证实。然而，ER应激在脂质诱导的肌肉IR中的作用仍存在争议。本研究的目的是测试棕榈酸酯诱导的IRE1α信号传导和TRB3表达是否会干扰成肌细胞中的胰岛素信号。将C2C12肌管暴露于棕榈酸酯，然后用胰岛素刺激。使用小干扰RNA（siRNA）转染下调TRB3和IRE1α。棕榈酸酯增加TRB3表达，激活IRE1α信号传导，并降低胰岛素依赖性Akt磷酸化。敲低TRB3或IRE1α并不能阻止棕榈酸酯对Akt磷酸化的抑制作用。我们的结果支持这样一种观点，即ER应激并非C2C12肌管中脂质诱导的IR的原因。
