Dysregulation of bile acid metabolism exacerbates diet-induced MASLD development in HuR deficient male mouse livers.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of hepatocellular carcinoma and liver transplantation worldwide, making identification of intervention strategies and therapeutic treatments essential to reducing morbidity and mortality associated with this disease. RNA binding proteins, like human antigen R (HuR), are ubiquitous and multi-faceted cell-stress regulators. HuR’s role in MASLD development is incompletely understood. This study aims to determine how hepatocyte HuR deficiency drives MASLD progression to Metabolic dysfunction-associated steatohepatitis (MASH). To model MASLD, we fed male hepatocyte-specific HuR knockout mice (HuRHep-/-) and WT control mice with the normal chow diet or the MASLD-inducing high fat, cholesterol, and fructose (HFCF) diet for 16 weeks. The liver transcriptomic profile was mapped using bulk RNA sequencing (RNA seq). After MASLD-inducing diet feeding, bile acid metabolism was modulated, while liver injury and fibrosis markers were increased in male HuRHep-/- mice, relative to WT. Our data suggests that hepatocyte HuR deficiency dysregulates bile acid metabolism and exacerbates MASLD progression.