title: Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans.
abstract: Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed "hepatic crown-like structures (hCLS)" in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.
authors.affiliation: Department of Organ Network and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan ; Medical Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Organ Network and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan ; Japan Science and Technology Agency, PRESTO, Tokyo, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suganami
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kuniha
authors.initials: K
authors.lastname: Konuma
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Marumoto
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Terai
authors.affiliation: Heart Life Hospital, Okinawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakugawa
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kanai
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Hamaguchi
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukaishi
authors.affiliation: Department of Home Economics, Otsuma Women's University, Tokyo, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Aoe
authors.affiliation: Department of Polymer Chemistry, Kyoto University Graduate School of Engineering, Kyoto, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Sakaida
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004002:Clodronic Acid / Q000494:pharmacology; D005234:Fatty Liver / Q000473:pathology*; D005260:Female; D006525:Hepatitis, Viral, Human / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008081:Liposomes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D010641:Phenotype; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism
chemical_list: D008081:Liposomes; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D004002:Clodronic Acid