Hyperlipidemia associated with obesity and type 2 diabetes (T2D) promotes excess hepatic lipid storage (steatosis) and endoplasmic reticulum (ER) stress, thereby reducing hepatic cell proliferation and survival. An important receptor tyrosine kinase controlling liver proliferation and survival is the epidermal growth factor receptor (EGFR). EGFR expression and activation are decreased during steatosis in humans and several animal models of obesity. Therefore, restoring EGFR activation in obesity-induced ER stress and diabetes could restore the liver's capacity for survival and regeneration. As an inducible feedback inhibitor of EGFR activity, mitogen-inducible gene 6 (Mig6) is a novel target for enhancing EGFR signaling during diet-induced obesity (DIO) and T2D. Thus, we hypothesized hepatic ER stress induces Mig6 expression and decreases EGFR activation during DIO and diabetes. We identified that Mig6 expression was increased during obesity-induced insulin resistance in C57Bl/6J mice fed a high fat diet. We also discovered that both pharmacological- and fatty acid-driven ER stress increased Mig6 expression and decreased EGF-mediated EGFR activation in primary rat hepatocytes and cell lines. Furthermore, siRNA-mediated Mig6 knockdown restored EGFR signaling and reduced caspase 3/7 activation during ER stress. Therefore, we conclude Mig6 is increased during ER stress in DIO, thereby reducing EGFR activation and enhancing cell death. The implications are the induction of Mig6 during DIO and diabetes may decrease hepatocyte survival, thus hindering cellular repair and regenerative mechanisms.

中文翻译：

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Mig6降低饱和脂肪酸诱导的内质网应激期间肝EGFR活化和存活

与肥胖症和2型糖尿病（T2D）相关的高血脂症会引起过多的肝脂质存储（脂肪变性）和内质网（ER）应激，从而降低肝细胞增殖和存活率。控制肝增殖和存活的重要受体酪氨酸激酶是表皮生长因子受体（EGFR）。在人类和一些肥胖动物模型的脂肪变性期间，EGFR表达和激活降低。因此，在肥胖引起的ER应激和糖尿病中恢复EGFR激活可以恢复肝脏的生存和再生能力。有丝分裂原诱导基因6（Mig6）作为EGFR活性的诱导反馈抑制剂，是在饮食引起的肥胖症（DIO）和T2D过程中增强EGFR信号传导的新靶标。从而，我们假设肝内质网应激可在DIO和糖尿病期间诱导Mig6表达并降低EGFR激活。我们确定，在高脂饮食的C57Bl / 6J小鼠中，肥胖诱导的胰岛素抵抗期间Mig6表达增加。我们还发现，药理和脂肪酸驱动的内质网应激均增加了原代大鼠肝细胞和细胞系中Mig6的表达并降低了EGF介导的EGFR激活。此外，在ER应激期间，siRNA介导的Mig6敲低恢复了EGFR信号传导并降低了caspase 3/7激活。因此，我们得出结论，在DIO内质网应激期间Mig6会增加，从而减少EGFR激活并增强细胞死亡。这意味着在DIO和糖尿病中Mig6的诱导可能会降低肝细胞存活率，从而阻碍细胞修复和再生机制。