Repositori URV

Author, as appears in the article.: Hernández-Alvarez MI; Sebastián D; Vives S; Ivanova S; Bartoccioni P; Kakimoto P; Plana N; Veiga SR; Hernández V; Vasconcelos N; Peddinti G; Adrover A; Jové M; Pamplona R; Gordaliza-Alaguero I; Calvo E; Cabré N; Castro R; Kuzmanic A; Boutant M; Sala D; Hyotylainen T; Oreši? M; Fort J; Errasti-Murugarren E; Rodrígues CMP; Orozco M; Joven J; Cantó C; Palacin M; Fernández-Veledo S; Vendrell J; Zorzano A

Department: Medicina i Cirurgia

URV's Author/s: Calvo Manso, Enrique / Fernandez Veledo, Sonia / Joven Maried, Jorge / Vendrell Ortega, Juan José

Keywords: Triglycerides Triacylglycerol Signal transduction Protein transport Protein lipid interaction Protein function Protein expression Protein deficiency Protein binding Priority journal Primary cell culture Physiology Phospholipid transfer Phospholipid synthesis Phosphatidylserines Phosphatidylserine Phosphatidylethanolamine Phenotype Pathology Nonhuman Nonalcoholic fatty liver Non-alcoholic fatty liver disease Nash Mouse model Mouse Mitofusin 2 Mitochondrion Mitochondrial proteins Mitochondrial protein Mitochondria Mice, inbred c57bl Mice Mfn2 protein, human Mfn2 Metabolism Mams Male Liver protection Liver fibrosis Liver diseases Liver disease Liver cell Liver cancer Liver biopsy Liver Lipid transport Lipid metabolism Inflammation Hypertriglyceridemia Humans Human tissue Human Hepatocytes Hepatitis Guanosine triphosphatase Gtp phosphohydrolases Endoplasmic reticulum stress Endoplasmic reticulum Disease models, animal Disease model Controlled study Cell growth C57bl mouse Article Apoptosis Animals Animal tissue Animal model Animal experiment Animal

Abstract: © 2019 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.

Thematic Areas: Odontología Medicina veterinaria Medicina iii Medicina ii Medicina i Interdisciplinar General medicine General biochemistry,genetics and molecular biology Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Cell biology Biochemistry, genetics and molecular biology (miscellaneous) Biochemistry, genetics and molecular biology (all) Biochemistry & molecular biology

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 00928674

Author's mail: enrique.calvo@urv.cat sonia.fernandez@urv.cat jorge.joven@urv.cat juanjose.vendrell@urv.cat

Author identifier: 0000-0003-2906-3788 0000-0003-2749-4541 0000-0002-6994-6115

Record's date: 2024-10-26

Papper version: info:eu-repo/semantics/acceptedVersion

Link to the original source: https://www.cell.com/cell/fulltext/S0092-8674(19)30396-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867419303964%3Fshowall%3Dtrue

Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Cell. 177 (4): 881-895.e17

APA: Hernández-Alvarez MI; Sebastián D; Vives S; Ivanova S; Bartoccioni P; Kakimoto P; Plana N; Veiga SR; Hernández V; Vasconcelos N; Peddinti G; Adrover A (2019). Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. Cell, 177(4), 881-895.e17. DOI: 10.1016/j.cell.2019.04.010

Article's DOI: 10.1016/j.cell.2019.04.010

Entity: Universitat Rovira i Virgili

Journal publication year: 2019

Publication Type: Journal Publications