The unfolded protein response (UPR) is associated with hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end, we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in the cellular stress response. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2-dependent enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in human and mouse livers with only male patients showing an accumulation of CRELD2 protein during the progression from non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and only male Creld2-deficient mice developing hepatic steatosis upon aging. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

中文翻译：

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未折叠蛋白反应期间的 Creld2 功能对于肝脏代谢稳态至关重要

未折叠蛋白反应 (UPR) 与肝脏代谢功能有关，但内质网 (ER) 紊乱如何影响代谢稳态尚不清楚。在这里，我们描述了富含半胱氨酸的 EGF 样结构域 2 (Creld2) 的生理功能，以前被描述为 ER 压力信号传感器 Atf6 的下游目标。为此，我们产生了Creld2 缺陷小鼠并通过注射衣霉素诱导 UPR。Creld2 通过与参与细胞应激反应的蛋白质的相互作用来增强蛋白质折叠并在 UPR 轴之间建立互连。因此，Creld2 促进对内质网应激的耐受性和急性应激的恢复。信使2- 缺乏导致 UPR 失调并导致在内质网应激条件下发生肝脂肪变性。此外，普遍定期审议的依赖于 Creld2 的增强有助于调节能量消耗。此外，我们在人类和小鼠肝脏中观察到性别二态性，只有男性患者在从非酒精性脂肪性肝病到非酒精性脂肪性肝炎的发展过程中表现出 CRELD2 蛋白的积累，并且只有缺乏 Creld2的雄性小鼠在衰老时出现肝脂肪变性。这些结果揭示了在 UPR 和代谢稳态之间的交叉点的 Creld2 功能，并表明慢性 ER 应激是男性脂肪肝疾病的基础机制。