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

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.

Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

“…Although research is paving the way for the development of therapeutics, the results of early clinical trials of drugs targeting single pathways have been mostly unsuccessful. Combining compounds that reduce lipid accumulation and hepatocellular injury has been proposed as a more suitable therapeutic strategy for this complex disease (Barbier-Torres et al, 2020;Barbier-Torres et al, 2017;Ertunc & Hotamisligil, 2016). Targeting multiple pathways is more likely to translate into successful outcomes (Friedman et al, 2018;Mardinoglu et al, 2018a;Mardinoglu et al, 2019).…”

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

“…Ideally, an approach that safely attenuates ETC without a full blockage could be more appropriate as a potential therapeutic. MCJ is the first identified endogenous negative regulator of Complex I and mitochondrial respiration, and it is abundantly expressed in some of the highly metabolically active tissues (e.g., liver, heart) 27 , 28 . Since the absence of MCJ causes chemoresistance, we investigated whether MCJ mimetics could restore MCJ function as a brake on the ETC in chemoresistant cancer cells.…”

“…In contrast, we show that ATP from glycolysis is dispensable, therefore upregulation of mitochondrial metabolism contributes to this mechanism of chemoresistance. Methylationcontrolled J protein (MCJ) encoded by the DNAJC15 gene, localizes on the inner membrane of mitochondria and acts as an endogenous brake on mitochondrial respiration by negatively regulating Complex I [25][26][27][28] . Retrospective and prospective studies have shown that loss of MCJ expression in tumors correlates with chemotherapy resistance and poor prognosis in breast and ovarian cancer patients 29,30 .…”

Treatment of Fatty Liver Disease: The Present and the Future

“…Inhibition of hepatic MCJ helps alleviates the inhibitory effect on ETC and prevents lipid accumulation. However increased beta-oxidation was associated with the accumulation of ROS which can lead to NAFLD progression, however, the activation of ETC diverts the ROS into the production of respiratory complexes reducing the damage caused due to ROS [ 39 ].…”

“…Barbier-Torres et al designed a small interfering ribonucleic acid (SiRNA) and a liver-specific delivery system to silence the MCJ and demonstrate the above-mentioned findings. His study also demonstrated that MCJ levels are higher in the hepatocytes of patients with NAFLD compared to healthy patients [ 39 ].…”