Premium
Creld2 function during unfolded protein response is essential for liver metabolism homeostasis
Author(s) -
Kern Paul,
Balzer Nora R.,
Blank Nelli,
Cygon Cornelia,
Wunderling Klaus,
Bender Franziska,
Frolov Alex,
Sowa JanPeter,
Bonaguro Lorenzo,
Ulas Thomas,
Homrich Mirka,
Kiermaier Eva,
Thiele Christoph,
Schultze Joachim L.,
Canbay Ali,
Bauer Reinhard,
Mass Elvira
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002713rr
Subject(s) - unfolded protein response , endoplasmic reticulum , steatohepatitis , tunicamycin , homeostasis , atf6 , fatty liver , steatosis , biology , endocrinology , medicine , microbiology and biotechnology , disease
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.