Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation

Lucía Barbier-Torres, Karen A. Fortner, Paula Iruzubieta, Teresa C. Delgado, Emily Giddings, Youdinghuan Chen, Devin Champagne, David Fernández-Ramos, Daniela Mestre, Beatriz Gomez-Santos, Marta Varela-Rey, Virginia Gutiérrez Juan, Pablo Fernández-Tussy, Imanol Zubiete-Franco, Carmelo García-Monzón, Águeda González-Rodríguez, Dhaval Oza, Felipe Valença-Pereira, Qian Fang, Javier Crespo, Patricia Aspichueta, Frederic Tremblay, Brock C. Christensen, Juan Anguita, María Luz Martínez-Chantar and Mercedes Rincón ()
Additional contact information
Lucía Barbier-Torres: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Karen A. Fortner: University of Vermont
Paula Iruzubieta: Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL)
Teresa C. Delgado: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Emily Giddings: University of Vermont
Youdinghuan Chen: Geisel School of Medicine at Dartmouth
Devin Champagne: University of Vermont
David Fernández-Ramos: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Daniela Mestre: University of the Basque Country UPB/EHU. Leioa, Biocruces Health Research Institute
Beatriz Gomez-Santos: University of the Basque Country UPB/EHU. Leioa, Biocruces Health Research Institute
Marta Varela-Rey: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Virginia Gutiérrez Juan: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Pablo Fernández-Tussy: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Imanol Zubiete-Franco: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Carmelo García-Monzón: Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, CIBERehd
Águeda González-Rodríguez: Liver Research Unit, Santa Cristina University Hospital, Instituto de Investigación Sanitaria Princesa, CIBERehd
Dhaval Oza: Alnylam Pharmaceuticals
Felipe Valença-Pereira: University of Colorado Denver
Qian Fang: University of Colorado Denver
Javier Crespo: Marqués de Valdecilla University Hospital, Research Institute Marqués de Valdecilla (IDIVAL)
Patricia Aspichueta: University of the Basque Country UPB/EHU. Leioa, Biocruces Health Research Institute
Frederic Tremblay: Alnylam Pharmaceuticals
Brock C. Christensen: Geisel School of Medicine at Dartmouth
Juan Anguita: CIC bioGUNE, Inflammation and Macrophage Plasticity laboratory, Bizkaia Science and Technology Park. Derio, Bizkaia, Spain; and Ikerbasque, Basque Foundation for Science
María Luz Martínez-Chantar: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas and Digestivas (CIBERehd). Bizkaia Science and Technology Park
Mercedes Rincón: University of Vermont

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Nonalcoholic 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.

Date: 2020
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DOI: 10.1038/s41467-020-16991-2

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