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

Paul Kern, Nora Reka Balzer, Franziska Bender, Alex Frolov, Jan-Peter Sowa, Lorenzo Bonaguro, Thomas Ulas, Christoph Thiele, Joachim L. Schultze, Ali Canbay, Reinhard Bauer, Elvira Mass

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Jan 29, 2020
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Received Date: 15th January 20

The unfolded protein response (UPR) is associated with the 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. 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. 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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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