Zebrafish are an excellent model for studying embryonic development and we are using the power of zebrafish genetics to define genes required for liver growth as well as to identify new models of liver diseases.

Fatty liver disease is emerging as an important liver pathology and is typically associated with obesity and type II diabetes. Additionally, fatty liver disease is associated with alcohol abuse and a number of inborn errors of metabolism. We have found a zebrafish mutant that develops fatty liver disease in the embryo, and have named it foie gras (fgr). The foie gras gene is well conserved in animals, but has no assigned sequence or motif that suggest its function. The primary focus of the Sadler lab is to understand the cellular function of foie gras, and to use the fgr mutant embryo as a model for studying fatty liver disease. In addition, we have developed other models of inherited and aquired liver disease in zebrafish, and are using these in conjunction with the fgr mutant to elucidate the pathways that are common to these disorders.

The second focus of our lab is to determine the genetic basis for liver growth in the embryo and during regeneration in adults, and is aimed at testing the hypothesis that a similar program may be responsible for growth control in both circumstances. We have carried out a screen to identify zebrafish mutant embryos which fail to undergo liver growth and are testing the genes responsible for the embryonic phenotype for their role in liver regeneration following partial hepatectomy. Our close collaboration with the Ukomadu lab (Brigham and Women's Hospital/Harvard Medical) has lead to the identification of the uhrf1 gene as an important regulator of liver growth in embryos and adults, and together with investigators at the Mount Sinai Hepatocellular Carcinoma Research Group, we are pursuing the possibility that uhrf1 also functions as an oncogene in hepatic cancer.