*Purpose: The escalating obesity crisis is a double-edged sword for the field of liver transplantation; higher rates of fatty liver disease increase both the demand for transplantation and the supply of suboptimal grafts. Indeed, mildly steatotic livers are increasingly used in clinical practice to address the widening liver shortage, yet a sizable proportion of donor livers with more severe levels of steatosis are discarded because the risks associated with transplanting them are poorly characterized. There is therefore a growing need to understand the molecular pathways that are differentially regulated across the gamut of healthy and steaotic livers to aide in the development of targeted interventions for improving liver quality pre-transplantation.

*Methods: We profiled the transcriptomes of 35 donor liver biopsies at two timepoints: pre-transplant and 90 minutes post-reperfusion. We classified n=20 of these samples as steaotic and compared their expression profiles with the group of n=15 non-steaotic samples.

*Results: Robust patterns of altered transcription were detected at both timepoints. While the fraction of differentially expressed genes was nearly twice as large pre-transplant than post, there was significant overlap across the two sets of genes. Furthermore, the direction and magnitude of observed transcriptional changes were highly consistent at both timepoints; model coefficients among differentially expressed genes were correlated at ρ = 0.96 (p < 0.001) across timepoints. The functional impact of these transcriptional changes was characterized using the Gene Ontology and KEGG Pathway databases. At both timepoints there was a significant enrichment of genes involved in metabolic pathways, protein synthesis, and genes encoding proteins that localize to the mitochondrial matrix. However, we also noted important functional differences by independently examining the fraction of differentially expressed genes unique to each timepoint. For example, there was an abundance Golgi-related genes involved with vesicle-mediated transport in the pre-transplant set, while the post-transplant set was over-represented for extracellular matrix organization pathways.

*Conclusions: Taken together, these results will improve our understanding of the molecular consequences that underlie sub-optimal livers and potentially lead to novel targets that may improve their function and viability for transplantation.

« Back to 2020 American Transplant Congress