title: Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression.
abstract: Liver sinusoidal endothelial cells (LSECs) are involved in the transport of nutrients, lipids, and lipoproteins, and LSEC injury occurs in various liver diseases including nonalcoholic fatty liver disease (NAFLD). However, the association between LSEC injury and NAFLD progression remains elusive. Accordingly, in this study, we aimed to elucidate the precise role of LSEC in the pathophysiology of NAFLD using two different mouse models, namely the choline-deficient, L-amino acid-defined and high-fat diet models. Administration of these diets resulted in liver metabolic dysregulation mimicking human NAFLD, such as steatosis, ballooning, lobular inflammation, and fibrosis, as well as central obesity, insulin resistance, and hyperlipidemia. LSEC injury appeared during the simple steatosis phase, and preceded the appearance of activated Kupffer cells and hepatic stellate cells (HSCs). These results indicate that LSEC injury may have a 'gatekeeper' role in the progression from simple steatosis to the early nonalcoholic steatohepatitis (NASH) stage, and LSEC injury may be necessary for the activation of Kupffer cells and HSCs, which in turn results in the development and perpetuation of chronic liver injuries. Taken together, our data provide new insights into the role of LSEC injury in NAFLD/NASH pathogenesis.
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyao
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kotani
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Tokiko
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kawai
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Manabe
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Abiru
authors.affiliation: Department of Forensic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002796:Choline Deficiency / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006949:Hyperlipidemias / Q000209:etiology; D007120:Immunochemistry; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000209:etiology; D008262:Macrophage Activation; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D056128:Obesity, Abdominal / Q000209:etiology; D013047:Specific Pathogen-Free Organisms
chemical_list: D015415:Biomarkers