Dataset Information

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

ABSTRACT: 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.

INSTRUMENT(S): Liquid Chromatography MS - Positive (LC-MS (Positive))

PROVIDER: MTBLS600 | MetaboLights | 2018-01-25

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 22

Publications

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.

Hernández-Alvarez María Isabel MI Sebastián David D Vives Sara S Ivanova Saška S Bartoccioni Paola P Kakimoto Pamela P Plana Natalia N Veiga Sónia R SR Hernández Vanessa V Vasconcelos Nuno N Peddinti Gopal G Adrover Anna A Jové Mariona M Pamplona Reinald R Gordaliza-Alaguero Isabel I Calvo Enrique E Cabré Noemí N Castro Rui R Kuzmanic Antonija A Boutant Marie M Sala David D Hyotylainen Tuulia T Orešič Matej M Fort Joana J Errasti-Murugarren Ekaitz E Rodrígues Cecilia M P CMP Orozco Modesto M Joven Jorge J Cantó Carles C Palacin Manuel M Fernández-Veledo Sonia S Vendrell Joan J Zorzano Antonio A

Cell 20190501 4

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, triglyce ...[more]

PMID: 31051106

Similar Datasets

Project description:Mardinoglu2014 - Genome-scale metabolic model (HMR version 2.0) - human hepatocytes (iHepatocytes2322) This model is described in the article: Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease. Mardinoglu A, Agren R, Kampf C, Asplund A, Uhlen M, Nielsen J. Nat Commun 2014; 5: 3083 Abstract: Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis. This model is hosted on BioModels Database and identified by: MODEL1402200003. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

			Action	DRS
	MAM03.mzML	Mzml
	MAM04.mzML	Mzml
	MAM07.mzML	Mzml
	MAM08.mzML	Mzml
	MAM11.mzML	Mzml