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Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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2019 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, no 4, p. 881-895.e17Article in journal (Refereed) Published
Abstract [en]

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.

Place, publisher, year, edition, pages
Cell Press , 2019. Vol. 177, no 4, p. 881-895.e17
Keywords [en]
MAMs, Mfn2, NASH, mitochondria, phosphatidylserine, phospholipid transfer
National Category
Gastroenterology and Hepatology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:oru:diva-74195DOI: 10.1016/j.cell.2019.04.010ISI: 000466843000010PubMedID: 31051106Scopus ID: 2-s2.0-85064698279OAI: oai:DiVA.org:oru-74195DiVA, id: diva2:1315280
Note

Funding Agencies:

CONACYT, Mexico  

MICINN Spain  

Coordenacao de Aperfeicoamento do Pessoal de Nivel Superior (CAPES)  

MINECO  SAF201675246R 

Generalitat de Catalunya (ICREA Academia)  2014SGR48  2017SGR696 

INFLAMES (ISCIII) PIE-14/00045 

CIBERDEM, ISCIII, INTERREG IV-B-SUDOE-FEDER (DIOMED)  SOE1/P1/E178 

"la Caixa'' Foundation  

Miguel Servet tenure-track program from the Fondo de Investigacion Sanitaria  CP10/00438  CPII16/00008 

ERD  

MINECO through the Centres of Excellence Severo Ochoa Award  

CERCA Programme of the Generalitat de Catalunya 

Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-06-19Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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