The research was conducted in genetic and nutritional animal models of steatohepatitis. Both models showed an accelerated progression of the disease when treated with SOD mimetics alone. It may be due to an accumulation of hydrogen peroxide caused by the SOD mimetics, which could not be metabolized by the antioxidant enzymes of the mitochondria due to the intrinsic depletion of mitochondrial GSH. The IDIBAPS investigators managed to maintain the antioxidant equilibrium by administrating a permeable form of glutathione (GSH) together with the SOD mimetics. The additional GSH protected hepatocytes against the accumulation of hydrogen peroxide, which was reduced by enzymes such as GSH peroxidase 1 (GSHPx1). This discovery offers clues for the development of new therapies.
Due to the rising prevalence of obesity worldwide, NASH constitutes a global health concern urgently requiring more effective therapies. The present work shows that therapeutic approaches using antioxidant drugs must take into account the equilibrium between SOD and GSH enzymes. Dr. José Carlos Fernández-Checa is now involved in a one year stay at the University of Sourthern California (USC), in Los Angeles, to share knowledge about steatohepatitis and animal models. His future research, at the United States and back with his team at IDIBAPS, will keep focusing on the central role of mitochondria and the oxidative stress in steatohepatitis, and undertanding the mechanisms regulating the critical balance among antioxidant strategies for optimal defense.