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

Kern, Paul; Balzer, Nora Reka; Blank, Nelli; Cygon, Cornelia; Wunderling, Klaus; Bender, F.; Frolov, Alex; Sowa, Jan-Peter; Bonaguro, Lorenzo; Ulas, Thomas; Homrich, Mirka; Kiermaier, Eva; Thiele, Christoph; Schultze, Joachim L.; Canbay, Ali; Bauer, Reinhard; Mass, Elvira

doi:10.1096/fj.202002713rr

Cited by 19 publications

(25 citation statements)

References 68 publications

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“…Indeed, a majority of genes altered by WD were equivalently up- or down-regulated across genotypes (Figure 5A-B; Figure S13). Top down-regulated genes included those previously associated with diabetes and obesity, such as Manf 28 and Creld2 29 that facilitate protein folding (Figure 5C), and Igfbp3 and Igfbp7 , two structurally similar proteins that regulate the bioavailability of IGFs and insulin. As noted for WD-fed MR-Intact mice, WD also down-regulated genes associated with extracellular matrix in SMC-MR-KO mice (Figure 5C, Table S13 and 14) and top up-regulated genes also included those implicated in diabetes and obesity, such as Cd36, Txnip, Angptl4, Cyp1a1 , and Fabp4 (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Dona

Hsu

Meuth

et al. 2022

Preprint

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Coronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Emerging evidence suggests development of heart failure with preserved ejection fraction in females with CMD and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the hypothesis that smooth muscle cell (SMC)-specific MR deletion prevents obesity-associated coronary and cardiac diastolic dysfunction in females. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Initial studies revealed that global MR blockade with spironolactone prevented impaired coronary vasodilation and diastolic dysfunction in obese females. Importantly, specific deletion of SMC-MR similarly prevented obesity-associated coronary and cardiac dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in multiple non-myocyte populations (B/T cells, macrophages, and endothelium), independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity.

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Section: Resultsmentioning

confidence: 99%

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Dona

Hsu

Meuth

et al. 2022

Preprint

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“…115,116 Recently, the crucial role of Creld2 was identified as a component that promotes protein folding and creates an interlink between the three UPR axes. 117 As such, it is involved in the UPR by interacting with chaperones and other proteins that regulate cellular stress response, and through this Creld2 confers tolerance to ER stress and recovery from acute stress. 117 The absence of Creld2 causes dysregulated UPR and the development of hepatic steatosis after ER stress induction, highlighting that proper Creld2 function is required for the maintenance of hepatic homeostasis under ER stress conditions.…”

Section: The Atf6α Axis In Nafldmentioning

confidence: 99%

“…117 The absence of Creld2 causes dysregulated UPR and the development of hepatic steatosis after ER stress induction, highlighting that proper Creld2 function is required for the maintenance of hepatic homeostasis under ER stress conditions. 117 Interestingly, CRELD2 protein accumulation during the progression from NAFLD to NASH was only observed in male patients, whilst Creld2 deficiency led to hepatic steatosis occurrence only in male mice, suggesting that Creld2 can serve as a gender-specific mechanism for NAFLD development after chronic ER stress. 117 Regarding the role of this pathway in Kupffer cells, ischemia/reperfusion in the liver and chemical treatment of macrophages in vitro induced ER stress response and ATF6 pathway activation, which led to the activation of the pro-inflammatory M1 phenotype of Kupffer cells.…”

Section: The Atf6α Axis In Nafldmentioning

confidence: 99%

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Flessa

Kyrou

Nasiri-Ansari

et al. 2022

J of Cellular Biochemistry

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress‐related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.

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“…5). Interestingly, the protein levels of two UPR-induced genes in the liver, hepcidin (48) and cysteine rich with EGF like domains 2 (CRELD2), an oncogene associated with HCC that promotes survival upon ER stress (49)(50)(51)(52), were increased in BDD-expressing mpPHH. These results for the first time show that ectopic BDD expression induces ER stress in human hepatocytes.…”

Section: Lentiviral Transduction Of Bdd Into Human Primary Hepatocyte...mentioning

confidence: 99%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

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Clotting Factor VIII (FVIII) is the protein deficient in hemophilia A (HA), an X chromosome-linked bleeding disorder affecting 24.6 per 100,000 males at birth. Scientists and clinical physicians have been striving hard to find a cure for this disease. Presently, HA therapy involves prophylactic infusion of plasma-derived or recombinant-derived FVIII. Recent clinical studies have reported success using recent adeno-associated-virus (AAV) vector mediated delivery of a FVIII gene. FVIII is a 330 kDa glycoprotein comprised of three domains (A1-A2-B-A3-C1-C2). The B domain is dispensable and B domain-deleted (BDD) FVIII is used in the clinic as an effective protein replacement therapy for HA. Previously, we observed that hydrodynamic tail vein injection of the BDD-FVIII vector resulted in FVIII aggregation and endoplasmic reticulum (ER) stress in murine livers. Additionally, mice that were exposed to transient ER stress and then fed a high fat diet (HFD) for 9 months developed hepatocellular carcinoma (HCC). Therefore, we deduced that ectopic transient expression of FVIII in hepatocytes of mice with subsequent HFD feeding may also develop HCC. Here, we tested hepatocyte expression of two BDD-FVIII variants in vivo. BDD-FVIII aggregates in the ER and induces hepatocyte apoptosis, and N6-FVIII is more efficiently folded and secreted from the ER and causes less hepatocyte apoptosis. We performed tail vein injections of vectors directing expression of BDD-FVIII or N6-BDD to hepatocytes of 6-week old mice. One week after injection, mice were fed 60% HFD for 65 weeks. We found that 50% of mice that received N6-BDD developed liver tumors; in contrast, 90% of mice given BDD-FVIII developed liver tumors. Of the mice injected with BDD-FVIII, 30% developed carcinomas and 60% developed adenomas. Similar masses were not observed in mice that received empty vector. These findings raise concerns about the safety of long-term ectopic expression of FVIII in hepatocytes during FVIII gene therapy

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

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 19 publications

References 68 publications

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD)

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

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