2. Academic Validation
  3. Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression

Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression

  • Cell Death Dis. 2024 Oct 23;15(10):770. doi: 10.1038/s41419-024-07151-1.
Rong Zhao # 1,  Zizhen Guo # 2,  Kaikai Lu 1,  Qian Chen 3,  Farooq Riaz 4,  Yimeng Zhou 5,  Luyun Yang 1,  Xiaona Cheng 1,  Litao Wu 1,  Kexin Cheng 1,  Lina Feng 6,  Sitong Liu 1,  Xiaodan Wu 1,  Minghua Zheng 7 8,  Chunyan Yin 9,  Dongmin Li 10 11 12
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China.
  • 2 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, P.R. China.
  • 4 Center for Cancer Immunology, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen, China.
  • 5 Department of Planned Immunization, Xi'an Center for Disease Control and Prevention, No. 599 Xiying Road, Yanta District, Xi'an, Shaanxi, China.
  • 6 GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, China.
  • 7 MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 8 Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
  • 9 Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China.
  • 10 Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, China. lidongm@mail.xjtu.edu.cn.
  • 11 Department of Biochemistry and Molecular Biology & Institute of Molecular and Translational Medicine, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China. lidongm@mail.xjtu.edu.cn.
  • 12 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, P.R. China. lidongm@mail.xjtu.edu.cn.
  • # Contributed equally.
PMID: 39438459 DOI: 10.1038/s41419-024-07151-1
Abstract

Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with Cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2HKO) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers Pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by Reactive Oxygen Species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in Pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.

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