未折叠蛋白反应
内质网
脂肪性肝炎
衣霉素
平衡
ATF6
脂肪肝
脂肪变性
生物
内分泌学
内科学
细胞生物学
医学
疾病
作者
Paul Kern,Nora Reka Balzer,Nelli Blank,Cornelia Cygon,Klaus Wunderling,F. Bender,Alex Frolov,Jan-Peter Sowa,Lorenzo Bonaguro,Thomas Ulas,Mirka Homrich,Eva Kiermaier,Christoph Thiele,Joachim L. Schultze,Ali Canbay,Reinhard Bauer,Elvira Mass
标识
DOI:10.1096/fj.202002713rr
摘要
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.
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