4.7 Article

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis

Journal

FASEB JOURNAL
Volume 35, Issue 10, Pages -

Publisher

WILEY
DOI: 10.1096/fj.202002713RR

Keywords

Creld2; ER stress; liver steatosis; NASH; UPR

Funding

  1. Fritz Thyssen Stiftung (Fritz Thyssen Foundation) [Az.10.18.2.029MN]
  2. Deutsche Forschungsgemeinschaft (DFG) [EXC2151-390873048, CA267/14-1]
  3. Bundesministerium fur Bildung und Forschung (BMBF) [01EA1809A]
  4. Daimler und Benz Stiftung (Daimler and Benz Foundation) [32-058/18]

Ask authors/readers for more resources

Creld2 plays a crucial role in regulating protein folding and cell stress response, enhancing the UPR and regulating energy expenditure. Lack of Creld2 may lead to UPR dysregulation and hepatic steatosis.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available