Mitochondrial dysfunction in nonalcoholic steatohepatitis (NASH): are there drugs able to improve it?

Abstract

Calorie-enriched diet and lack of work out are causing a worldwide surge of obesity and insulin resistance (IR), which favors lipid accretion in the liver (i.e. hepatic steatosis, or fatty liver). Indeed, IR in the adipose tissue increases lipolysis and the entry of free fatty acids (FFAs) in the liver, whereas IR-associated hyperinsulinemia favors de novo synthesis of FFAs and triacylglycerol (TAG) molecules (i.e. lipogenesis). Fortunately, some hormonal and metabolic adaptations are set up to restrain fat accumulation in the liver, such as an increase in fatty acid oxidation (FAO). Although fatty liver is a benign condition in majority of patients, it can develop in some individuals into nonalcoholic steatohepatitis (NASH), which can further evolve into cirrhosis. Currently, the mechanisms responsible for this progression are still poorly understood but could involve the overproduction of reactive oxygen species (ROS) and a large array of deleterious cytokines that promote cell death, inflammation and fibrosis. Importantly, mitochondria appear to be a major site of ROS generation within the hepatocytes during NASH, which could be related to lower glutathione (GSH) import in these organelles, increased local expression of cytochrome P450 2E1 (CYP2E1) and enhanced leakage of electrons from the mitochondrial respiratory chain (MRC) caused by boosted FAO and concomitant MRC impairment. A vicious circle can ensue because ROS can damage the mitochondrial DNA and key components of the MRC, thus further impairing the MRC and augmenting electron leakage and ROS formation. In theory, the ideal drug for the treatment of NASH would reduce fat accretion in the liver and decrease cytokine and ROS overproduction. Although this drug does not exist at the moment, there are some synthetic and natural derivatives presenting metabolic and/or antioxidative effects that can directly or indirectly improve mitochondrial function during NASH.