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Here, we describe the physiological function of Cysteine\u2010rich with EGF\u2010like domains 2 (Creld2), previously characterized as a downstream target of the ER\u2010stress signal transducer Atf6. To this end, we generated\n                    <jats:italic>Creld2<\/jats:italic>\n                    \u2010deficient 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.\n                    <jats:italic>Creld2<\/jats:italic>\n                    \u2010deficiency leads to a dysregulated UPR and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2\u2010dependent 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\u2010alcoholic fatty liver disease to non\u2010alcoholic steatohepatitis and only male\n                    <jats:italic>Creld2<\/jats:italic>\n                    \u2010deficient 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.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002713rr","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T05:04:54Z","timestamp":1632287094000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Creld2 function during unfolded protein response is essential for liver metabolism homeostasis"],"prefix":"10.1096","volume":"35","author":[{"given":"Paul","family":"Kern","sequence":"first","affiliation":[{"name":"Developmental Biology of the Immune System Life &amp; Medical Sciences (LIMES) Institute University of Bonn Bonn Germany"},{"name":"Developmental Genetics &amp; Molecular Physiology Life &amp; Medical Sciences (LIMES) Institute University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora R.","family":"Balzer","sequence":"additional","affiliation":[{"name":"Developmental Biology of the Immune System Life &amp; 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