Investigating the Efficacy and Mechanism of JMY104 in Nonalcoholic Fatty Liver Disease

Hsiao-Chen Huang (黃筱真) 1, Yun-Ti Chen 2, Ting-Wen Zeng 1, Jinn-Moon Yang1,2#, Shey-Cherng Tzou1,3#

1 Department of Biological Science & Technology, National Yang Ming Chiao Tung University

2Institute of Bioinformatics and Systems Biology, National Yan-ing Chiao Tung University

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of chronic liver diseases that encompass simple steatosis to non-alcoholic steatohepatitis (NASH) which may eventually progress to liver fibrosis and cirrhosis. Diagnostic markers and treatment options for NAFLD are currently limited, in particular, no FDA-approved drug is available for NASH. JMY104 is a novel IRAK-1 inhibitor identified by Professor. Jinn-Moon Yang’s lab of the National Yang Ming Chiao Tung University. We show that JMY104 is an effective treatment of liver steatosis in cell and mouse models. We validated the candidate genes identified in our mouse model of NAFLD. We further tested whether JMY104 could treat a diet-induce NASH in mouse. Our results indicate that (1) lipid accumulation increased in HepG2 cells deficient in GENE C, GENE D, GENE F, GENE I and FASN but decreased in GENE B knockout cells. (2) GENE B may be directly involved in JMY104-mediated suppression of lipid accumulation in HepG2 cells, and GENE I may lead to reduced the effect of JMY104 in reducing lipid accumulation. (3) JMY104 could reduce collagen deposition in CDAA (choline-deficient amino acid-define diet supplemented with 45% fat and 0.1% cholesterol) diet-induced NASH model. (4) JMY104 reduced symptoms (lipid droplets, hepatocyte ballooning and NAS scores) associated with western diet-induced NASH model. Thus, JMY104 may be repurposed as a highly effective therapeutic agent for NAFLD and further development is warranted.