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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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is considered the major health epidemic with an estimated 25% worldwide prevalence
We investigated the role of MCJ in fatty liver disease using MCJ-deficient (MCJ KO) mice and the methionine- and choline-deficient (MCD) diet mouse model of non-alcoholic steatohepatitis (NASH) where lipid accumulation in the liver causes steatosis followed by fibrosis
To examine whether loss of MCJ could impact liver fibrosis, WT and MCJ KO mice were maintained on the MCD diet for 3 weeks
Summary
Nonalcoholic fatty liver disease (NAFLD) is considered the major health epidemic with an estimated 25% worldwide prevalence. Increasing mitochondrial respiratory activity in the liver could enhance degradation of fatty acids, thereby preventing their accumulation and liver disease progression. This pathway has not been extensively considered therapeutically for the treatment of NAFLD because of the potential increase in the generation of reactive oxygen species (ROS) as a result of enhanced β-oxidation. Using siRNA as a therapeutic approach we show that treatment with different formulations of siMCJ after the onset of the disease reduces liver steatosis and fibrosis in multiple mouse models These results, together with the increased levels of MCJ in liver of NAFLD patients we report here, suggest that MCJ is emerging as an alternative target for treatment of NASH
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