2. Academic Validation
  3. FOSL2 deficiency delays nonalcoholic steatohepatitis progression by regulating LY6D-mediated NLRP3 activation

FOSL2 deficiency delays nonalcoholic steatohepatitis progression by regulating LY6D-mediated NLRP3 activation

  • Hum Cell. 2022 Nov;35(6):1752-1765. doi: 10.1007/s13577-022-00760-y.
Pei-Xin Hu  # 1 2,  Mei-Yan Sheng  # 3,  Yan-Ping Liu 4,  Chun-Qing Zhang 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, No. 324, Jingwuwei 7 Road, Huaiyin District, Jinan, 250021, Shandong Province, People's Republic of China.
  • 2 Department of Gastroenterology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, People's Republic of China.
  • 3 Department of Pulmonary and Critical Care Medicine, Shandong Public Health Clinical Center Affiliated to Shandong University, Jinan, 250013, Shandong, People's Republic of China.
  • 4 Department of Radiology, Qilu Hospital of Shandong University, No. 107, Wenhua West Road, Lixia District, Jinan, 250012, Shandong Province, People's Republic of China. liuyanping6210@163.com.
  • 5 Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, No. 324, Jingwuwei 7 Road, Huaiyin District, Jinan, 250021, Shandong Province, People's Republic of China. zhchunqing@outlook.com.
  • # Contributed equally.
PMID: 35930135 DOI: 10.1007/s13577-022-00760-y
Abstract

Lymphocyte antigen 6 family member D (LY6D) was enhanced specifically in senescent cells, while its effects on Pyroptosis, a programmed cell death, remains unknown. The goal of this study was to assess the role of LY6D in the mediation of Pyroptosis during nonalcoholic steatohepatitis (NASH). After screening out LY6D as a specific liver fibrosis-associated gene using the GSE55747 dataset from the GEO database, we established a NASH mouse model using methionine and choline deficient-diet feeding and an in vitro model using lipopolysaccharide (LPS)-treated hepatocytes. LY6D was overexpressed in NASH livers as well as in LPS-treated hepatocytes. Silencing of LY6D inhibited NASH-associated hepatocyte Pyroptosis. With the aid of bioinformatics analysis, promoter-luciferase reporter and ChIP-qPCR assays, we identified FOSL2 as an upstream transcription factor of LY6D. FOSL2, which was highly expressed in NASH, promoted LY6D transcription by binding to the promoter of LY6D. Depletion of FOSL2 significantly inhibited NASH-associated hepatocyte Pyroptosis, which was significantly reversed after overexpression of LY6D. Moreover, the promotion of hepatocyte Pyroptosis by the FOSL2/LY6D axis was significantly attenuated by specific inhibition of NLRP3. These findings suggesting that FOSL2/LY6D axis may be a key molecular axis and a potential target for NASH therapeutics.

Keywords

FOSL2; LY6D; NLRP3; Nonalcoholic steatohepatitis; Pyroptosis.

Figures
Products