Grant: Project Grant

Non-alcoholic Fatty Liver Disease (NAFLD) is present in 30% of Canadians, reaching >70% in those with diabetes and obesity. Many progress from reversible stages of liver fat accumulation to inflammation (non-alcoholic steatohepatitis-NASH) and fibrosis; to irreversible stages of cirrhosis and cancer. No medicines are yet approved for NAFLD but the most promising are long-acting glucagon-like peptide-1 receptor agonists (GLP-1-RA) which reduced NASH activity in most patients but did not reduce fibrosis, the primary determinant of long-term survival. There is thus great need for anti-fibrosis drugs, which we've just identified to be YAP/TAZ NUAK inhibitors (NUAK-i). The major problems with previous studies are: 1) inability to dissect the different components of this complex disease including mitochondria dysfunction, toxic fat accumulation, inflammation and fibrosis; and elucidate the specific mechanisms each drug actually works on each disease component; and 2) directly test drugs on the different stages of human NAFLD livers whereby each stage likely requires specific drug combinations, recognizing that mouse models may not completely mimic human NAFLD nor accurately predict clinical response to treatment. We surmounted these problems by: 1) developing thin liver slices assays that independently assess fat accumulation (Aim 1), mitochondria function & survival (Aim 2), and fibrosis (Aim 3); and 2) obtaining fresh liver samples from patients undergoing bariatric surgery that span the reversible stages of NAFLD (normal, steatosis, NASH) and various stages of fibrosis. This provides a unique opportunity to test our hypothesis that GLP-1RA and NUAK-i can block or reverse each disease component of NAFLD. This work will: 1) unequivocally show the specific cellular events matched to disease genes and NAFLD stage rescued by GLP-1-RAs and NUAK-i; and 2) provide a precision medicine approach to treat each NAFLD stage with insights directly translatable to clinical trials.