NFATc4 mediates ethanol-triggered hepatocyte senescence. (10th October 2021)

• Record Type: Journal Article
• Authors: Wu, Ruoman; Wang, Xinqi; Shao, Yunyun; Jiang, Yiming; Zhou, Ying; Lu, Chunfeng
• Is Part Of: Toxicology letters. Volume 350(2021)
• Page Start: 10
• Page End: 21
• Publication Date: 2021-10-10
• Subjects: Alcoholic liver disease -- Hepatocyte -- Senescence -- NFATc4 -- PPAR; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.06.018
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: NFATc4 expression is enhanced in ethanol-treated hepatocytes. NFATc4 knockdown alleviates alcoholic liver injury. NFATc4 knockdown abolishes alcohol-triggered hepatocyte senescence. NFATc4 deficiency rescues PPARγ expression in ethanol-damaged hepatocytes. PPARγ deficiency is required for NFATc4-mediated hepatocyte senescence. Abstract: Background: Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. Methods: Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. Results: NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated β-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. Conclusions: This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.