Grant: Project Grant

Liver disease has a significant impact on the Canadian population affecting more than 8 million Canadians. Muscle wasting and hepatic encephalopathy (HE; complex neuropsychiatric disorder) are serious complications of chronic liver disease (CLD; cirrhosis) affecting 80% of patients. These complications increase hospital admissions and mortality, hence adding to the already significant economic burden on health care systems. Liver transplantation, the only curative treatment for CLD, is a limiting therapeutic option due to a shortage of available livers. Therefore, development of alternative therapeutic strategies to prevent complications and prolong survival until a liver becomes available for transplantation is crucial. Inflammation and ammonia are major factors implicated in the development of HE. Muscle wasting may predispose to the development of HE since the muscle plays a vital compensatory role in ammonia detoxification. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and brain-derived neurotrophic fator (BDNF) are factors implicated in the regulation of muscle mass. We hypothesize that ammonia and inflammation-induced PGC-1alpha downregulation in cirrhosis adversely leads to muscle mass loss (through decreased BDNF) and, consequently, to HE, which are attenuated with exercise training and omega-3 fatty acids supplementation. We will use in vitro, in vivo model systems and cirrhotic patients to verify our hypothesis. Results of this study will clarify the role of PGC-1alpha/BNDF in the pathogenesis of cirrhosis-related muscle mass loss and HE. Finally, as the pathophysiological mechanisms are identified, insights for efficient therapeutic strategies will be uncovered, not only to improve the quality of life of cirrhotic patients while waiting for a healthy liver, but also to lead to a better outcome following liver transplantation.