1570-P: A Human Unique Role of RNA-Binding Protein HuR in Nonalcoholic Steatohepatitis

Introduction & Objective: Overnutrition-induced obesity heightens the risk of cardiometabolic diseases, necessitating an understanding of how it disrupts gene expression for preventive strategies against obesity-related diseases. The RNA-binding protein human antigen R (HuR) has demonstrated a crucial role in post-transcriptional gene regulation, exhibiting protective effects against nonalcoholic steatohepatitis (NASH) in mouse models. However, the HuR's protective role in human NASH remains uncertain due to potential differences in HuR binding between human and mouse untranslated regions. This study aims to elucidate the role of HuR in human NASH using chimeric mice with humanized livers and cultured human cells.

Methods: Knocking down human HuR was performed in humanized mouse livers, and the impact was assessed by RNA-seq. In human cells, HuR overexpression and co-overexpression with peroxisome proliferator-activated receptor alpha (PPARA) were conducted. Additionally, Western blotting was employed to analyze HuR protein expression in liver samples obtained from healthy donors and NASH patients.

Results: Knocking down human HuR in the humanized liver led to the upregulation of RXRA and fatty acid oxidation-related (FAO) genes. Concurrently, overexpression of HuR in human cells suppressed RXRA protein expression. Furthermore, HuR inhibited PPARA-induced expression of FAO genes by suppressing the PPARA cofactor RXRA. Western blotting analysis revealed elevated HuR and reduced RXRA protein levels in the livers of NASH patients.

Conclusion: This study indicate that HuR is induced in human NASH and suppresses RXRA and FAO genes, suggesting HuR may aggravate NAFLD progression in humans, which is opposite to HuR studies using traditional mouse genetic models.