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.
Recent and intriguing human and mouse studies have indicated that the unfolded protein response is a new and important mechanism of FLO pathophysiology, however it is not known whether this pathway contributes to this disease or whether it protects against it. The work proposed here is the first to utilize zebrafish to study the pathophysiology of steatosis, with the long-term goal of using this system to develooJheram~utics to combat it.
|Bambino, Kathryn; Zhang, Chi; Austin, Christine et al. (2018) Inorganic arsenic causes fatty liver and interacts with ethanol to cause alcoholic liver disease in zebrafish. Dis Model Mech 11:|
|Shtraizent, Nataly; DeRossi, Charles; Nayar, Shikha et al. (2017) MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. Elife 6:|
|Wang, Shuang; Miller, Sophie R; Ober, Elke A et al. (2017) Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research. Curr Top Dev Biol 124:161-195|
|DeRossi, Charles; Vacaru, Ana; Rafiq, Ruhina et al. (2016) trappc11 is required for protein glycosylation in zebrafish and humans. Mol Biol Cell 27:1220-34|
|Goessling, Wolfram; Sadler, Kirsten C (2015) Zebrafish: an important tool for liver disease research. Gastroenterology 149:1361-77|
|Vacaru, Ana M; Di Narzo, Antonio Fabio; Howarth, Deanna L et al. (2014) Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish. Dis Model Mech 7:823-35|
|Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335|
|Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie et al. (2014) In vivo cell biology in zebrafish - providing insights into vertebrate development and disease. J Cell Sci 127:485-95|
|Tsedensodnom, Orkhontuya; Vacaru, Ana M; Howarth, Deanna L et al. (2013) Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease. Dis Model Mech 6:1213-26|
|Chu, Jaime; Mir, Alexander; Gao, Ningguo et al. (2013) A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation. Dis Model Mech 6:95-105|
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