| Nonalcoholic Fatty Liver Disease (NAFLD) is the most common liver pathology and a comorbidity of obesity. The histologic progression of NAFLD initiates with lipid accumulation in hepatocytes (steatosis). This is reversible, but can progress to irreversible liver damage. The molecular mechanisms involved in how steatosis predisposes the liver to further damage are not well understood. Thus, the identification of new proteins, pathways, and mechanisms involved in the acquisition of steatosis is important to better understand the pathophysiology of NAFLD. To this end we identified the zebrafish mutant foie gras (foigr), which has a phenotype of hepatomegaly, steatosis, and embryonic lethality at 6 days-post-fertilization (dpf). The gene mutated in foigr, trappc11, is involved in vesicle transport between the endoplasmic reticulum and the Golgi apparatus. Ongoing research is focused on identifying the link between the hepatic secretory pathway and steatosis. Steatosis mainly results from an increase of lipids transported to the liver from adipose tissue. To this end, foigr mutants do not get steatosis from a lipodystrophy or decreased adipose development as adipocytes develop beginning at 12 dpf. Here we characterized adipose tissue development for the first time in zebrafish, showing that adipocytes first appear intertwined with the pancreas and then in subsequent compartments and is correlated to fish size rather than temporal cues. Since extrinsic factors didn't lead to steatosis in foigr, we previously looked at liver-intrinsic pathways such as the unfolded protein response (UPR) by knocking down one arm of the UPR pathway, Atf6, which attenuates steatosis in foigr. Here, we also downregulated the other two arms of the UPR in zebrafish, Ern1 and Eif2&agr;k3, which results in liver hypoplasia, and possible musculoskeletal and neuronal abnormalities. We found that zebrafish can tolerate knockdown of multiple arms of the UPR suggesting that this model of UPR attenuation may be ideal for studying the role of the UPR in development and disease. Future studies will focus on knocking down Ern1 and Eif2&agr;k3 in foigr alone and in combination with Atf6 to better understand the role of the UPR in the acquisition of steatosis in foigr.. |
