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A Novel Mouse Model of Nonalcoholic Steatohepatitis Suggests that Liver Fibrosis Initiates around Lipid-Laden Macrophages.
Ichimura-Shimizu, Mayuko; Tsuchiyama, Yosuke; Morimoto, Yuki; Matsumoto, Minoru; Kobayashi, Tomoko; Sumida, Satoshi; Kakimoto, Takumi; Oya, Takeshi; Ogawa, Hirohisa; Yamashita, Michiko; Matsuda, Satoru; Omagari, Katsuhisa; Taira, Shu; Tsuneyama, Koichi.
Affiliation
  • Ichimura-Shimizu M; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Food Science and Nutrition, Nara Women's University, Nara, Japan.
  • Tsuchiyama Y; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Morimoto Y; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Matsumoto M; Department of Molecular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Kobayashi T; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Sumida S; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Kakimoto T; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Oya T; Department of Molecular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Ogawa H; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Yamashita M; Morphological Laboratory Science, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
  • Matsuda S; Department of Food Science and Nutrition, Nara Women's University, Nara, Japan.
  • Omagari K; Division of Nutritional Science, Graduate School of Human Health Science, University of Nagasaki, Nagasaki, Japan.
  • Taira S; Faculty of Food and Agricultural Sciences, Fukushima University, Fukushima, Japan.
  • Tsuneyama K; Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Molecular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: tsuneyama.koichi@
Am J Pathol ; 192(1): 31-42, 2022 01.
Article in En | MEDLINE | ID: mdl-34710382
ABSTRACT
While the interaction of cells such as macrophages and hepatic stellate cells is known to be involved in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), the mechanism remains unclear. This study employed a high-fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis to investigate the pathogenesis of fibrosis. Two mouse strains C57BL/6J, the one susceptible to obesity, and A/J, the one relatively resistant to obesity, developed hepatic histologic features of NASH, including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis, after 9 weeks of HFCC diet. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in the C57BL/6J mice. A/J mice fed HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light was used to visualize the Maltese cross, cholesterol crystals within the aggregated macrophages. Fibrosis developed in a ring shape from the periphery of the aggregated macrophages such that the starting point of fibrosis could be visualized histologically. Matrix-assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine [P-181 (11Z)/180] and phosphatidylethanolamine [180/202 (11Z, 14Z)], in aggregated macrophages adjacent to the fibrotic lesions. In conclusion, the HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Non-alcoholic Fatty Liver Disease / Lipids / Macrophages Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2022 Type: Article Affiliation country: Japan

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Non-alcoholic Fatty Liver Disease / Lipids / Macrophages Type of study: Prognostic_studies Limits: Animals Language: En Journal: Am J Pathol Year: 2022 Type: Article Affiliation country: Japan