This proposal outlines a plan to investigate the role of ceramides in alcohol-induced lipid droplet biogenesis and in post-liver transplant alcoholic liver disease (ALD) recurrence. The research will use novel in vitro and in vivo model systems to investigate the hypothesis that the ceramide synthetic enzyme ceramide synthase 6 (CerS6) regulates alcohol-induced lipid droplet biogenesis through the transcriptional regulation of the lipid droplet protein, Perilipin 2 (PLIN2). Furthermore, this proposal will investigate the association between CerS6 upregulation in alcoholic steatosis and graft loss in post-transplant recurrent ALD. The researcher aims 1) to determine the mechanisms by which CerS6 regulates PLIN2 and lipid droplet biogenesis; 2) to determine the effects of hepatocyte-specific CerS6 ablation on lipid and glucose homeostasis in experimental ALD and 3) to determine if CerS6 expression predicts graft loss in post-transplant recurrent ALD. To accomplish these Specific Aims, the researcher proposes to use CRISPR/Cas9 genetically engineered mice and human ethanol-metabolizing VL17A cells to perform comprehensive metabolic phenotyping, lipidomics analyses, and biochemical and functional assays. In addition, the researcher aims to examine if CerS6 immunohistochemical expression predicts graft loss in patients with recurrent ALD post- transplant. Results of this project will provide evidence for targeting CerS6 as a diagnostic and therapeutic biomarker in post-transplant ALD recurrence.
Fifty percent of alcoholic liver disease patients have alcohol recidivism within the first five years of transplantation, and advanced fibrosis or graft loss occurs in approximately 20% of those patients. Currently, there are no tools to predict which of these patients are likely to develop recurrent advanced liver disease. This project aims to understand the molecular mechanisms of post-transplant recurrent alcoholic liver disease and investigate biomarkers associated with disease recurrence and severity. Developing such biomarkers will lead to new therapeutics for patients with alcohol recidivism post-liver transplant.
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| Pickett-Blakely, Octavia; Young, Kimberly; Carr, Rotonya M (2018) Micronutrients in Nonalcoholic Fatty Liver Disease Pathogenesis. Cell Mol Gastroenterol Hepatol 6:451-462 |
