BraveHEART: Improvig Nature by Addressing Bioactive Dietary Polyphenols to Mitochondria for the Protection of Cardiac Complications in Non-Alcoholic Fatty Liver Disease

Overview

Project Summary

NAFLD/NASH prevalence is estimated to be about 25-40%, with a tendency to increase in the following years. The first symptomatic manifestations are frequently associated with extra-hepatic severe complications, such as CVD (12). Cardiovascular diseases (CVDs) it self are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. In fact, CVD are a significantly greater cause of death in NAFLD and some authors concluded that cardiac dysfunction is also associated with visceral fat accumulation – itself frequently associated with NAFLD (13). High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes and NAFLD, that in turn can lead to cardiac injury.
The published data so far indicates that NAFLD is associated with cardiovascular alterations, which involve increased accumulation of fat in cardiomyocytes while at the same time mitochondrial activity is decreased. Among other, contractile perturbances can be a consequence of this disarranged cardiac metabolic state (13).Hence, one approach for the treatment of hepatic diseases and associated serious extra-hepatic diseasesinvolves the targeting of mitochondria oxidative damage and improvement of their bioenergetic capacity (8). The heavy social and economic burden imposed by NAFLD and related complications underscores the importance of developing effective pharmacological interventions, but unfortunately, there are still no FDA-approved effective therapies. So, a high unmet need in terms of effective therapeutic strategy exists for liver diseases worldwide.
Several studies were performed with antioxidant supplements, however, they were inconclusive or contradictory. We hypothesized that certain antioxidant compounds failed to show beneficial effects on NAFLD/NASH because not enough antioxidant molecules reach mitochondria. Also, antioxidant administration may fail because most of them only act as free-radical scavengers, which is not enough to improve mitochondrial function. This innovative and relevant project hypothesizes that mitochondrial-directed AntiOxCIN4 prevents/delay NAFLD/NASH-induced cardiac alterations in a rodent model.

Main Goals

Despite the overall incidence of chronic liver and associated serious extra-hepatic diseases, there is still no effective treatment. So, a high unmet need exists in terms of effective therapeutic strategy. This innovative and relevant project hypothesizes that mitochondrial-directed AntiOxCIN4 prevents/delay NAFLD/NASH-induced cardiac alterations in a rodent model. We aim to demonstrate that the mitochondrial-directed antioxidant (AntiOxCIN4) prevents/delay cardiac mitochondrial dysfunction and oxidative damage in vitro and in vivo relevant models NAFLD/NASH, approaching AntiOxCIN4 from future clinical use. This project is designed with two main goals: a) validate the beneficial cardiac effects of AntiOxCIN4 in a 2D and 3D in vitro relevant cellular models towards supraphysiologic concentrations of free fatty acids (FFA); b) Evaluate the effects of AntiOxCIN4 (2.5 mg/day/animal) on the NAFLD-associated  cardiac alterations, the major cause of death in NASH patients, using a mouse (male and female) model of high fat high sugar (HFHS)-induced simples steatosis (NASH).

Project Details