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OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Lien Verboom (UGent) , Arne Martens (UGent) , Dario Priem (UGent) , Esther Hoste (UGent) , Mozes Sze (UGent) , Hanna-Kaisa Vikkula (UGent) , Lisette Van Hove (UGent) , Sofie Voet (UGent) , Jana Roels (UGent) , Jonathan Maelfait (UGent) , et al.
(2020) CELL REPORTS. 30(7). p.2237-2247
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Abstract
Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC.
Keywords
NF-KAPPA-B, TNF-ALPHA, MICE, NECROPTOSIS, ACTIVATION, STEATOHEPATITIS, DEFICIENT, DELETION, RECEPTOR, FIBROSIS

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MLA
Verboom, Lien, et al. “OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.” CELL REPORTS, vol. 30, no. 7, 2020, pp. 2237–47.
APA
Verboom, L., Martens, A., Priem, D., Hoste, E., Sze, M., Vikkula, H.-K., … van Loo, G. (2020). OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis. CELL REPORTS, 30(7), 2237–2247.
Chicago author-date
Verboom, Lien, Arne Martens, Dario Priem, Esther Hoste, Mozes Sze, Hanna-Kaisa Vikkula, Lisette Van Hove, et al. 2020. “OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.” CELL REPORTS 30 (7): 2237–47.
Chicago author-date (all authors)
Verboom, Lien, Arne Martens, Dario Priem, Esther Hoste, Mozes Sze, Hanna-Kaisa Vikkula, Lisette Van Hove, Sofie Voet, Jana Roels, Jonathan Maelfait, Laura Bongiovanni, Alain de Bruin, Charlotte Scott, Yvan Saeys, Manolis Pasparakis, Mathieu Bertrand, and Geert van Loo. 2020. “OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.” CELL REPORTS 30 (7): 2237–2247.
Vancouver
1.
Verboom L, Martens A, Priem D, Hoste E, Sze M, Vikkula H-K, et al. OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis. CELL REPORTS. 2020;30(7):2237–47.
IEEE
[1]
L. Verboom et al., “OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis,” CELL REPORTS, vol. 30, no. 7, pp. 2237–2247, 2020.
@article{8658985,
  abstract     = {Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC.},
  author       = {Verboom, Lien and Martens, Arne and Priem, Dario and Hoste, Esther and Sze, Mozes and Vikkula, Hanna-Kaisa and Van Hove, Lisette and Voet, Sofie and Roels, Jana and Maelfait, Jonathan and Bongiovanni, Laura and de Bruin, Alain and Scott, Charlotte and Saeys, Yvan and Pasparakis, Manolis and Bertrand, Mathieu and van Loo, Geert},
  issn         = {2211-1247},
  journal      = {CELL REPORTS},
  keywords     = {NF-KAPPA-B,TNF-ALPHA,MICE,NECROPTOSIS,ACTIVATION,STEATOHEPATITIS,DEFICIENT,DELETION,RECEPTOR,FIBROSIS},
  language     = {eng},
  number       = {7},
  pages        = {2237--2247},
  title        = {OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis},
  url          = {http://dx.doi.org/10.1016/j.celrep.2020.01.028},
  volume       = {30},
  year         = {2020},
}

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