Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation
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Published:2020-07-03
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Barbier-Torres Lucía, Fortner Karen A., Iruzubieta Paula, Delgado Teresa C., Giddings Emily, Chen YoudinghuanORCID, Champagne DevinORCID, Fernández-Ramos David, Mestre Daniela, Gomez-Santos Beatriz, Varela-Rey Marta, de Juan Virginia Gutiérrez, Fernández-Tussy Pablo, Zubiete-Franco Imanol, García-Monzón Carmelo, González-Rodríguez Águeda, Oza Dhaval, Valença-Pereira Felipe, Fang Qian, Crespo Javier, Aspichueta Patricia, Tremblay Frederic, Christensen Brock C.ORCID, Anguita JuanORCID, Martínez-Chantar María LuzORCID, Rincón MercedesORCID
Abstract
AbstractNonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate β-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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