Chronic liver diseases such as non-alcoholic fatty liver disease and alcoholic liver disease are significant health concerns worldwide. Despite knowledge of disease features and environmental causes, we lack understanding of the genetic factors and molecular mechanisms that can be targeted for liver disease therapeutics. Many of these factors are also essential during embryonic development and organogenesis. Here, we use liver development in zebrafish as a model and paradigm for the discovery of regulators impacting liver disease pathogenesis. A chemical screen in zebrafish identified the endocannabinoid (EC) signaling pathway as a regulator of liver development. This pathway was previously implicated in animal models of chronic liver disease, but little was known about its role in development. We generated cannabinoid receptor mutant zebrafish using genome editing and show that EC signaling is required for hepatic maturation and outgrowth, but not earlier milestones such as hepatic specification. Mutant zebrafish also exhibited defects in lipid processing, and we found that methionine metabolism, involving sterol regulatory element binding proteins (SREBPs), is an integral mediator in this process. In a separate study, we used zebrafish to functionally annotate a panel of candidate genes identified by a genome-wide association study (GWAS) for elevated liver plasma enzymes, which are used as a clinical liver disease marker. We prioritized GWAS candidates for morpholino knockdown in zebrafish and discovered effects on hepatic progenitor and hepatocyte development as well as differences in susceptibility to metabolic and toxic injury. Our approach can be applied to other GWAS data sets to rapidly assess additional characteristics during zebrafish development. The work presented here gives valuable insight into how regulators of hepatogenesis also have roles in metabolism and disease. / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/17463147 |
| Date | 17 July 2015 |
| Creators | Liu, Leah |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | open |
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