ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2021
Creld2 function during unfolded protein response is essential for liver metabolism homeostasis.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 28 citations in OpenAlex.
- Integrative omics profiling of CRELD2 in ccRCC: a nexus of genetics, prognosis, and tumor microenvironment.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Paediatric proteomic signatures of cardiometabolic disease-associated traits predict adult disease outcomes.Nature metabolism · 2026Article
- Multi-omics network reconstruction with collaborative graphical lasso.Bioinformatics (Oxford, England) · 2026Article
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- TCF19 drives a broad transcriptional program that potentiates optimal innate and adaptive functions of antiviral NK cells.Nature immunology · 2025Article
- Endothelial cell-secreted bone targeting exosomes promote angiogenesis coupling with osteogenesis via the PERK-ATF4-CRELD2 pathway.Stem cell research & therapy · 2025Article
- Article
- Endoplasmic reticulum stress-induced CRELD2 promotes APMAP-mediated activation of TGF-β/SMAD and NF-κB pathways in esophageal squamous cell carcinoma.Frontiers in immunology · 2025Article
- Multi-tissue gene expression profiling of cows with a genetic predisposition for low and high milk urea levels.Animal biotechnology · 2024Article
- Molecular characterization of the ER stress-inducible factor CRELD2.Cell biochemistry and biophysics · 2024Article
- Periodic heat waves-induced neuronal etiology in the elderly is mediated by gut-liver-brain axis: a transcriptome profiling approach.Scientific reports · 2024Article
- Updated mechanisms of MASLD pathogenesis.Lipids in health and disease · 2024Review
- Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?Current issues in molecular biology · 2024Review
- Cardioprotective effects of the angiocrine CRELD2 after ischemic injury.Nature cardiovascular research · 2024Article
- Cysteine-rich with EGF-like domains 2 (CRELD2) is an endoplasmic reticulum stress-inducible angiogenic growth factor promoting ischemic heart repair.Nature cardiovascular research · 2024Article
- Angiogenic factor induced by ER stress promotes tissue repair after myocardial infarction.Nature cardiovascular research · 2024Article
- Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice.Basic research in cardiology · 2023Article
- CRELD2, endoplasmic reticulum stress, and human diseases.Frontiers in endocrinology · 2023Review
- Aging and aging-related diseases: from molecular mechanisms to interventions and treatments.Signal transduction and targeted therapy · 2022Review
- Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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