Repositori URV

Identificador: imarina:5097887

Handle: https://hdl.handle.net/20.500.11797/imarina5097887

Autores:
Hernández-Alvarez MISebastián DVives SIvanova SBartoccioni PKakimoto PPlana NVeiga SRHernández VVasconcelos NPeddinti GAdrover AJové MPamplona RGordaliza-Alaguero ICalvo ECabré NCastro RKuzmanic ABoutant MSala DHyotylainen TOreši? MFort JErrasti-Murugarren ERodrígues CMPOrozco MJoven JCantó CPalacin MFernández-Veledo SVendrell JZorzano A

Resumen:
© 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.