ETI

Pilot Project

Kirsten Sadler-Edepli
Kirsten Sadler-Edepli, PhD
Assistant Professor Medicine, Liver Diseases
Assistant Professor Developmental and Regenerative Biology
Mount Sinai School of Medicine

A Novel Screen for Therapeutics to Treat Fatty Liver Disease

Accumulation of lipid in hepatocytes (steatosis) is one of the most frequent outcomes of obesity and type II diabetes, and it is estimated that 1/3 of Americans have fatty liver disease (FLD). While simple steatosis is reversible, many patients with FLD go on to develop steatohepatitis, which can lead to liver cirrhosis requiring liver transplant. Additionally, steatosis is a co-morbidity factor for other hepatic diseases, affects hepatic drug metabolism and impairs the regenerative capacity of the liver. Treatments for FLD are limited: the only available options are life style changes and a few compounds to improve hepatic insulin sensitivity. Thus, new therapies for FLD are essential and novel approaches are sought. We propose to utilize Drosophila and zebrafish to screen for candidate therapeutic compounds directed at FLD. Drosophila on a high-sugar diet develop signs of type II diabetes, including increased lipid accumulation in the fat-body. As sugar metabolism is tied to development, flies on a high-sugar diet also have a delayed time to pupation, and we have demonstrated that this is linked to insulin signaling. Using this phenotype as an indicator of insulin sensitivity, we will carry out a screen to identify compounds that accelerate the time-to-pupation of Drosophila on a high-sugar diet, indicating improved insulin signaling. Positive compounds will then be assessed for their ability to reduce fat-body lipid accumulation in Drosophila. Next, we have developed 4 new models of FLD in zebrafish larvae, including the mutant foie gras, tunicamycin treatment, acute alcohol exposure and fasting. We will determine the toxicity of the candidate compounds in zebrafish and then test their efficacy at reducing steatosis in each of these models. Compounds which are effective in decreasing the number of larvae that develop steatosis in one or more of our zebrafish models will be further explored for their ability to alter molecular markers of liver function, as measured by quantitative PCR. Therefore, this screen combines the high-throughput screening potential of Drosophila with detailed analysis of FLD in a vertebrate model, with the aim of identifying potential therapies for patients with this disease.