For those affected globally by Non-Alcoholic fatty liver disease (NAFLD), hope is on the horizon as scientist have discovered a new target and new therapy that shows promising results in preclinical mouse models. The disease is one of the causes of chronic liver disease worldwide and is linked to the soaring prevalence of obesity and type 2 diabetes, according to Elsevier. Currently there is no approved drug to battle the disease.
NAFLD which affects 25 percent of the global population is characterized by the accumulation of fat in the liver that can led to fibrosis and eventually Non-Alcoholic Steatohepatitis (NASH), an advance phase of NAFLD that causes liver failure and eventually death. It remains the major form of chronic liver disease.
The lead author of the research, Professor Mercedes Rincon of the Department of Immunology and Microbiology of the University of Colorado, said that the incidence is higher in people who are obese, but it is not restricted to them.
Rincon and other researchers at the Anschutz Medical Campus, University of Colorado, in their study focused on Methylation-Controlled J (MCJ) Protein as a target for NASH. This protein lives in the mitochondria, the engine of the cells, where lipids are burned in the liver. MCJ acts as a brake on the metabolic activity of the mitochondria. Patients with NAFLD often have higher MCJ levels in their livers.
The result revealed that MCJ is emerging as an alternative target for treating NASH and NAFLD.
“Currently, most leading therapeutic drugs undergoing clinical trials for NASH are small molecules given as a systemic treatment. 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,” Rincon said.
But MCJ is not critical for life under normal conditions, so Rincon’s team decided to eliminate this metabolic brake in the liver to increase fat burning and minimize the accumulation of lipids and the development of fibrosis. They used siRNA or Small Interfering RNA to silence MCJ in the liver. This is an emerging therapeutic approach that has shown success in treating some liver diseases.
To test if siRNA for MCJ (called siMCJ) could be a potential therapeutic against NAFLD, mice in preclinical studies were fed a high-fat, high fructose diet. After months on the diet, the mice developed fatty liver. Then they were treated regularly with siMCJ or a placebo.
The siMCJ group had lower levels of lipids and fibrosis in their livers compared to the control group. Using this treatment, similar reductions in lipid content and fibrosis were seen in another model on a low protein diet.
“We showed that MCJ-deficient mice are resistant to the development of fatty liver and NASH. Importantly, 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,”Rincon said.
