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

The unfolded protein response (UPR) is associated with the metabolic function of the liver, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of the Cysteine-rich with EGF-like domains 2 (Creld2), which has been previously characterized as a downstream target of the ER-stress signal transducer Atf6. Creld2 enhances protein folding and degradation through its interaction with proteins involved in UPR, thereby, promoting tolerance of chronic stress and recovery from acute stress. Using a genetic knockout model, we show that Creld2-deficiency leads to a dysregulated UPR, and causes the development of hepatic steatosis in male mice, while females are protected. We observed this sex dimorphism also in humans with fatty liver disease, with only males showing an accumulation of CRELD2 protein in the liver. 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. Analysis of liver RNA expression of mice from two different in vivo models for non-alcoholic fatty liver induction. Dietary in vivo model mice were fed either control diet (CD) or high fat diet (HFD) for 12 weeks, or HFD for 8 weeks followed by CD for 4 weeks (HFD>CD). Pharmacological in vivo model mice were administered either a sucrose control, thapsigargin (TG, 0.5 mg/kg) or tunicamycin (TM, 1mg/kg) via intraperitoneal injection and sacrificed after 48 hours.