Takuya Sakaguchi Laboratory

Research

Our laboratory utilizes zebrafish to investigate the pathogenesis of human liver diseases including biliary atresia (BA) and nonalcoholic steatohepatitis (NASH).  Through an unbiased genome-wide forward genetic screen, we have isolated new zebrafish mutants that model these human liver diseases. 

Biliary atresia, the most common infantile liver disease, is characterized by the occlusion of the entire biliary tree.  As the disease progresses, many BA patients will require liver transplantation.  We are investigating the molecular mechanisms underlying biliary atresia-like phenotypes in BA-like zebrafish mutants by using our innovative computational algorithms to quantify subtle difference in three-dimensional biliary branching patterns.  This work will help to understand the molecular pathology of BA.

We are also analyzing new zebrafish mutants that show NASH-like phenotypes.  NASH is a common liver disease and the initial stage of NASH is hepatic steatosis (accumulation of excess lipids), which progresses to liver inflammation and fibrosis.  Our zebrafish NASH-like mutant similarly initiates hepatic steatosis and progresses into liver inflammation and fibrosis.   Since NASH can result in end-stage liver cirrhosis and liver cancer, it is important to establish efficient treatment to halt or reverse the progression of this disease.  Using the Nash-like zebrafish mutant, we are able to investigate the molecular mechanisms underlying its pathogenesis.  This work will shed new light on previously unappreciated molecular targets for the therapy of NASH. 

Selected Publications

Dimri M., Bilogan C., Pierce LX., Naegele G., Vasanji A., Gibson l., McClendon A., Tae K., Sakaguchi T.F. (2017) Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepaticbiliary network branching in zebrafish. 144(14):2595-2605 PMCID:PMC5536925

Nussbaum J.M., Liu L.J., Hasan S.A., Schaub M., McClendon A., Stainier D.Y.R. and Sakaguchi T.F.  (2013) Homeostatic generation of reactive oxygen species protects the zebrafish liver from steatosis. Hepatology, 58(4):1326-1338.  PMCID: PMC3791216  

Schaub, M., Nussbaum, J.,  Verkade, H., Ober, H.,  Stainier, D.Y.R., and Sakaguchi, T.F. (2012)  Mutation of zebrafish Snapc4 is associated with loss of the intrahepatic biliary network.  Developmental Biology, 363(1):128-37. PMCID: PMC3711868

Sakaguchi, T.F.*, Sadler, K.C., Crosnier, C., Stainier, D.Y.R.* (2008)  Endothelial signals modulate hepatocyte apico-basal polarization in zebrafish. Curr. Biol. 18(20):1565-1571.  PMCID: PMC 2720033*Co-correspondence

Sakaguchi, T., Kikuchi, Y., Kuroiwa, A., Takeda, H., Stainier, D.Y.R. (2006)  The yolk syncytial layer regulates myocardial migration by influencing extracellular matrix assembly in zebrafish. Development 133(20):4063-4072