Expression of SREBF2 and HMGCR discriminates the viability of steatotic grafts for human liver transplantation

Hepatic steatosis presents a rising challenge in liver transplantation (LT), yet the precise underlying players remain incompletely understood. As steatosis reflects the accumulation of several types of lipids, including cholesterol, which has emerged as a key player in metabolic-dysfunction associated fatty liver disease, we aimed to characterize the content of lipids and the expression of cholesterol metabolic genes in liver biopsies before (pre-LT) and after LT (post-LT), with the ultimate goal of identifying factors that may impact graft loss and the overall outcomes of LT. Lipid content and cholesterol-related genes in pre- and post-LT graft biopsies, clinical outcome, and survival within the first year after LT were analyzed in 174 patients. Unlike free fatty acids (FFA) and triglycerides, total and free cholesterol (FC) levels are maintained in pre- and post-LT samples. Increased FC and FFA levels in pre-LT samples were associated with early allograft dysfunction (EAD). The increase in the expression of cholesterol regulatory genes SREBF2 and HMGCR in pre-LT samples was identified as a potential risk factor of death after LT, particularly with SREBF2, whose expression is associated with EAD and graft loss (GL). Collectively, these data link the expression of genes involved in the synthesis of cholesterol to LT-related mortality. These findings may translate to an increased application of marginal steatotic grafts in LT, thereby promoting a safe outcome.