Increasing cellular NAD+ protects hepatocytes against palmitate-induced lipotoxicity by preventing PARP-1 inhibition and the mTORC1-p300 pathway activation

• DOI: 10.1152/ajpcell.00946.2024
• Publication Date: 2025-01-28T06:30:07Z
• Authors: Rui Guo; Yanhui Li; Qing Song; Rong Huang; Xiaodong Ge; Natalia Nieto; Yuwei Jiang; Zhenyuan Song

This study explores the mechanisms of palmitate-induced hepatotoxicity, highlighting the role of PARP-1 downregulation in triggering the mTORC1-p300 pathway and resultant hepatocyte cell death. It further reveals that enhancing cellular NAD+ levels through either precursor supplementation or NNMT inhibitors prevents lipotoxicity by restoring PARP-1 activity. Finally, the study identifies that the TLR4-NF-κB activation mediates palmitate-induced PARP-1 suppression and offers potential therapeutic insights for metabolic liver diseases caused by lipotoxicity.