{
  "abstract": "Background Autophagy is critical for cellular homeostasis. Autophagy related 14 (ATG14) is a key regulator of autophagy initiation; however, its role in hepatocyte survival remains poorly understood. This study aimed to investigate the hepatocyte-specific function of ATG14 in vivo.Methods We generated Atg14 hepatocyte-specific knockout (HepKO) mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into Atg14 floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet. Blood and tissue samples were collected for biochemical and histological analyses.Results Atg14 HepKO mice develop severe hepatomegaly under normal dietary conditions. ATG14 deficiency leads to hepatic injury, inflammation and fibrosis. Multiple forms of cell death, including apoptosis and pyroptosis, increase significantly. When challenged with a Western diet for 4 weeks, Atg14 HepKO mice exhibit exacerbated hepatic injury, inflammation and fibrosis despite no significant lipid droplet accumulation in the liver. Transcriptomic analysis reveals upregulation of several cell death pathways, including pyroptosis, apoptosis and necroptosis. Further biochemical and microscopic analyses validate the induction of multiple cell death pathways. In addition, NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in Atg14 HepKO mouse livers and ATG14-deficient hepatocytes.Conclusion Our data suggest that ATG14 is required for maintaining hepatocyte identity, survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly, tissue injury, inflammation and fibrosis.",
  "authors": [
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Hyeong-Geug Kim"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Menghao Huang"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Shen Wang"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China"
      ],
      "name": "Yang Zhang"
    },
    {
      "affiliations": [
        "Luddy School of Informatics, Computing, and Engineering, Indiana University Indianapolis, Indianapolis, Indiana, USA"
      ],
      "name": "Kailing Li"
    },
    {
      "affiliations": [
        "Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Sheng Liu"
    },
    {
      "affiliations": [
        "Luddy School of Informatics, Computing, and Engineering, Indiana University Indianapolis, Indianapolis, Indiana, USA"
      ],
      "name": "Chuanpeng Dong"
    },
    {
      "affiliations": [
        "Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Xiuxiu Yang"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "East and West Cancer Center, Dunsan Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea"
      ],
      "name": "Jung-Hyo Cho"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Kushan Chowdhury"
    },
    {
      "affiliations": [
        "Electron Microscopy Center, Indiana University, Bloomington, Indiana, USA"
      ],
      "name": "Barry Stein"
    },
    {
      "affiliations": [
        "Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Luddy School of Informatics, Computing, and Engineering, Indiana University Indianapolis, Indianapolis, Indiana, USA",
        "Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Jun Wan"
    },
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA",
        "Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Xiaocheng Charlie Dong"
    }
  ],
  "title": "Autophagy related 14 protects against liver injury by inhibiting multiple cell death pathways",
  "uid": "826c2646-8bec-59cd-93d1-2f457b8d9157"
}