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

• Published in: Nature communications Vol. 11; no. 1; pp. 3360 - 15
• Main Authors: Barbier-Torres, Lucía, Fortner, Karen A., Iruzubieta, Paula, Delgado, Teresa C., Giddings, Emily, Chen, Youdinghuan, Champagne, Devin, 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., Anguita, Juan, Martínez-Chantar, María Luz, Rincón, Mercedes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 13/95; 14/19; 14/34; 14/63; 38/22; 38/77; 38/88; 631/154/51/2053; 64/110; 692/4020/4021/1607/2750; Adult; Aged; Animal models; Animals; Damage accumulation; Datasets as Topic; Degeneration; Diet, High-Fat - adverse effects; Disease Models, Animal; Drug development; Electron transport chain; Fatty acids; Fatty Acids - metabolism; Fatty liver; Female; Fibrosis; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; HSP40 Heat-Shock Proteins - antagonists & inhibitors; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; J protein; Lipids; Liver; Liver - cytology; Liver - drug effects; Liver - pathology; Liver diseases; Male; Methylation; Middle Aged; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - pathology; Oxidation; Oxidation-Reduction - drug effects; Primary Cell Culture; RNA, Small Interfering - administration & dosage; RNA-Seq; Science; Science (multidisciplinary); siRNA; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16991-2

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. Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.