Departments of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden.
Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
J Lipid Res. 2018 Jul;59(7):1148-1163. doi: 10.1194/jlr.M080788. Epub 2018 May 23.
Ceramides contribute to obesity-linked insulin resistance and inflammation in vivo, but whether this is a cell-autonomous phenomenon is debated, particularly in muscle, which dictates whole-body glucose uptake. We comprehensively analyzed lipid species produced in response to fatty acids and examined the consequence to insulin resistance and pro-inflammatory pathways. L6 myotubes were incubated with BSA-adsorbed palmitate or palmitoleate in the presence of myriocin, fenretinide, or fumonisin B1. Lipid species were determined by lipidomic analysis. Insulin sensitivity was scored by Akt phosphorylation and glucose transporter 4 (GLUT4) translocation, while pro-inflammatory indices were estimated by IκBα degradation and cytokine expression. Palmitate, but not palmitoleate, had mild effects on Akt phosphorylation but significantly inhibited insulin-stimulated GLUT4 translocation and increased expression of pro-inflammatory cytokines and Ceramides, hexosylceramides, and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro-inflammatory indices. Inhibition of sphingolipid pathways led to marked changes in cellular lipids, but did not prevent palmitate-induced impairment of insulin-stimulated GLUT4 translocation, suggesting that palmitate-induced accumulation of deleterious lipids and insulin resistance are correlated but independent events in myotubes. We propose that muscle cell-endogenous ceramide production does not evoke insulin resistance and that deleterious effects of ceramides in vivo may arise through ancillary cell communication.
神经酰胺有助于体内肥胖相关的胰岛素抵抗和炎症，但这是否是一种细胞自主性现象存在争议，特别是在肌肉中，它决定着全身的葡萄糖摄取。我们全面分析了脂肪酸反应产生的脂质种类，并研究了其对胰岛素抵抗和促炎途径的影响。用 BSA 吸附的棕榈酸或棕榈油酸孵育 L6 肌管，并在存在甘露庚酮糖、芬维 A 胺或伏马菌素 B1 的情况下。通过脂质组学分析确定脂质种类。胰岛素敏感性通过 Akt 磷酸化和葡萄糖转运蛋白 4（GLUT4）易位来评分，而促炎指数通过 IκBα 降解和细胞因子表达来估计。棕榈酸，但不是棕榈油酸，对 Akt 磷酸化有轻微影响，但显著抑制胰岛素刺激的 GLUT4 易位，并增加促炎细胞因子的表达和 神经酰胺、己糖神经酰胺和鞘氨醇-1-磷酸显著增加。棕榈酸与胰岛素敏感性呈负相关，与促炎指数呈正相关。鞘脂途径的抑制导致细胞脂质发生明显变化，但不能防止棕榈酸诱导的胰岛素刺激的 GLUT4 易位受损，这表明棕榈酸诱导的有害脂质积累和胰岛素抵抗是肌管中相关但独立的事件。我们提出，肌肉细胞内源性神经酰胺的产生不会引起胰岛素抵抗，而体内神经酰胺的有害作用可能通过辅助细胞通讯产生。
