Inhibition of MCJ Transmembrane Protein Studied as NAFLD Treatment

A research team at the University of Colorado Anschutz Medical Campus published an article in Nature Communications showing promising results for a new target and therapy for Nonalcoholic Fatty Liver Disease (NAFLD) for which there is currently no approved drugs. 

NAFLD is the most common chronic liver disease and is caused by an accumulation of fat in the liver, which can lead to fibrosis. It can develop into Non-Alcoholic Steatohepatitis (NASH), which can cause liver failure and death.  "NAFLD is a major health issue right now, a real epidemic with no treatment. It affects about 25% of the world population," says lead author Mercedes Rincon. "The incidence is higher in those who are obese, but it is not restricted to them."

The team looked at the Methylation-Controlled J protein as a target for NASH. The protein lives in the mitochondria and acts as a brake on the metabolic activity of the organelle.  Patients with NAFLD are often found to have high levels of MCJ in their livers.  Rincón’s team was interested in eliminating the metabolic brake in order to increase fat burning and prevent or minimize the accumulation of fatty tissue in the liver which can lead to fibrosis. Their approach was to use small Interfering RNA to silence MCJ in the liver, which is an emerging treatment approach that has shown some success in other liver diseases.

In order to confirm if silencing MCJ through SiRNA would work as a therapeutic against NAFLD, mice were fed high fructose, high-fat diet to fatten their livers. After being treated with placebos and SiMCJ, the group with SiMCJ showed lower levels of lipids and fibrosis than the control group.

"We showed that MCJ-deficient mice are resistant to the development of fatty liver and NASH," Rincón adds. A crucial aspect of this therapy is the delivery to the right part of the liver, which they accomplished by combining the SiRNA with a sugar derivative that binds directly to hepatocytes. 

"Currently, most leading therapeutic drugs undergoing clinical trials for NASH are small molecules given as a systemic treatment," Rincon says. "Our data show, in contrast, that the use of siRNA to reduce the levels of MCJ in the liver may constitute an alternative therapeutic strategy."