Protein secretion is among? the most important functions of hepatocytes. Defects in the secretory pathway can have serious consequences~ For instance, patients with congenital disorders of glycosylation in which secreted proteins are not properly glycosylated and trafficked, have serious and multisystemic problems, including hepatic steatosis that a rapidly progresses to fibrosis requiring liver transplant in very young children. Additionally, stress in the secretory pathway, called ER stress, is associated with fatty liver disease resulting from obesity and alcohol abuse and is a new and exciting line of inquiry in this burgeoning field. Importantly, drugs that improve protein folding, which are currently in clinical use, are proposed as therapies for fatty liver disease (FLO). We are using zebrafish to study the mechanism by which defects in the secretory pathway, namely protein glycosylation and the unfolded protein response, contribute to FLO. We have developed 2 new models of COG in zebrafish. One of these is the foie gras (fgr) mutant, that we identified in an effort to identify vertebrate models of liver diseases through a forward genetic screen in zebrafish. fgr mutants develops steatosis. The fgr gene is recessive embryonic lethal and is well conserved in all animals, but has not been studied in any species other than zebrafish. The gene does not encode any sequence motifs that implicate a specific function or family, and thus it represents a potential novel player in FLO. Our recent data demonstrates an essential role for Fgr in protein N-glycosylation, and fgr mutants display features of COG.
The first aim of this work is to characterize the fgr allele and to define the defects in organelle function and protein trafficking that occur as a result oUgr mutation.
Our second aim i s to investigate the link between the unfolded protein response and steatosis in our zebrafish models of COG and alcohol exposure. Using the power of zebrafish genetics, we will determine the role of each unfolded protein response branch in steatosis in fgr mutants and alcohol-treated fish. This will conclusively demonstrate whether this pathway is protective or pathologic in the development of steatosis.
Fatty liver disease (FLD) is the most common liver disease in the United States and affects over 1/3 of the nearly 200 million Americans categorized as overweight or obese. The prevalence of FLD places it at the forefront of public health concern. Our laboratory is committed to understanding the etiologies of FLD via zebrafish disease models.
Showing the most recent 10 out of 23 publications
