Ca²⁺ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca²⁺ regulate synthesis and post-translational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca²⁺ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca²⁺-insulin and insulin-Ca²⁺ signaling pathways in obesity remain poorly understood. Here we show that the kinetics of insulin-initiated intracellular (initial) Ca²⁺ release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a GLP-1 analog, reversed lipid-induced inhibition of intracellular Ca²⁺ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca²⁺ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca²⁺ release, at least partially, via lipid reduction in hepatocytes which then restored hormone-regulated cytoplasmic Ca²⁺ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca²⁺ signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.

中文翻译：

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由于脂肪变性导致的 Ca2+ 信号受损介导了 Alstrom 综合征小鼠的肝脏胰岛素抵抗，该抵抗被 GLP-1 类似物治疗逆转

Ca ²⁺信号传导在包括胰岛素在内的激素对肝脏代谢的调节中起关键作用。细胞质 Ca ^{2+ 的}变化调节胰岛素通路中关键信号蛋白的合成和翻译后修饰。新出现的证据表明，在从肥胖啮齿动物模型中分离的载脂肝细胞中，肝细胞胞内 Ca ²⁺信号发生改变。改变Ca的机制²⁺ -胰岛素和胰岛素的Ca ²⁺信号传导在肥胖途径仍然知之甚少。在这里，我们展示了胰岛素引发的细胞内（初始）Ca ²⁺的动力学在肥胖的 Alström 综合征小鼠的脂肪变性肝细胞中，内质网的释放显着受损。此外，艾塞那肽（一种 GLP-1 类似物）逆转了脂质诱导的对脂肪变性肝细胞内 Ca ²⁺释放动力学的抑制，而不影响细胞内 Ca ²⁺释放的总含量。艾塞那肽通过减少肝细胞中的脂质，至少部分逆转脂质诱导的细胞内 Ca ²⁺释放抑制，然后恢复激素调节的细胞质 Ca ²⁺信号传导和胰岛素敏感性。该数据为 Ca ²⁺的重要作用提供了额外的证据肥胖相关肝脂质稳态受损和胰岛素信号通路中的信号通路。它还强调了 GLP-1 类似物在用于治疗与肝脂肪变性相关的 2 型糖尿病时的潜在优势。