Molecular mechanisms of post-transplant recurrent alcoholic liver disease

PROJECT SUMMARY This proposal outlines a plan to investigate the role of ceramide synthase 6 in alcohol-induced lipid droplet biogenesis and as a potential diagnostic biomarker of pre- and 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 its use as an early biomarker of 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-ceramides are implicated in early pre- and post-transplant human ALD. To accomplish these Specific Aims, the researcher proposes to use 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 and its ceramide derivatives can be used to diagnose early ALD in both pre- and 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.