PMID- 24349208 OWN - NLM STAT- MEDLINE DCOM- 20141012 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 12 DP - 2013 TI - Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. PG - e82163 LID - 10.1371/journal.pone.0082163 [doi] LID - e82163 AB - 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. FAU - Itoh, Michiko AU - Itoh M AD - Department of Organ Network and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Kato, Hideaki AU - Kato H AD - 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. FAU - Suganami, Takayoshi AU - Suganami T AD - Department of Organ Network and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan ; Japan Science and Technology Agency, PRESTO, Tokyo, Japan. FAU - Konuma, Kuniha AU - Konuma K AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Marumoto, Yoshio AU - Marumoto Y AD - Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. FAU - Terai, Shuji AU - Terai S AD - Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. FAU - Sakugawa, Hiroshi AU - Sakugawa H AD - Heart Life Hospital, Okinawa, Japan. FAU - Kanai, Sayaka AU - Kanai S AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Hamaguchi, Miho AU - Hamaguchi M AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Fukaishi, Takahiro AU - Fukaishi T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Aoe, Seiichiro AU - Aoe S AD - Department of Home Economics, Otsuma Women's University, Tokyo, Japan. FAU - Akiyoshi, Kazunari AU - Akiyoshi K AD - Department of Polymer Chemistry, Kyoto University Graduate School of Engineering, Kyoto, Japan. FAU - Komohara, Yoshihiro AU - Komohara Y AD - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Takeya, Motohiro AU - Takeya M AD - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Sakaida, Isao AU - Sakaida I AD - Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. FAU - Ogawa, Yoshihiro AU - Ogawa Y AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131211 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Liposomes) RN - 0 (MC4R protein, mouse) RN - 0 (Receptor, Melanocortin, Type 4) RN - 0813BZ6866 (Clodronic Acid) SB - IM MH - Animals MH - Chronic Disease MH - Clodronic Acid/pharmacology MH - Fatty Liver/*pathology MH - Female MH - Hepatitis, Viral, Human/pathology MH - Humans MH - Inflammation/pathology MH - Lipid Metabolism/drug effects MH - Liposomes/metabolism MH - Liver/drug effects/*pathology/ultrastructure MH - Liver Cirrhosis/pathology MH - Macrophages/drug effects/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Middle Aged MH - Non-alcoholic Fatty Liver Disease MH - Phenotype MH - Receptor, Melanocortin, Type 4/metabolism PMC - PMC3859576 COIS- Competing Interests: HK is an employee of Shionogi & Co. Ltd. The authors have declared that no competing interests exist. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2013/12/19 06:00 MHDA- 2014/10/13 06:00 PMCR- 2013/12/11 CRDT- 2013/12/19 06:00 PHST- 2013/08/01 00:00 [received] PHST- 2013/10/21 00:00 [accepted] PHST- 2013/12/19 06:00 [entrez] PHST- 2013/12/19 06:00 [pubmed] PHST- 2014/10/13 06:00 [medline] PHST- 2013/12/11 00:00 [pmc-release] AID - PONE-D-13-31501 [pii] AID - 10.1371/journal.pone.0082163 [doi] PST - epublish SO - PLoS One. 2013 Dec 11;8(12):e82163. doi: 10.1371/journal.pone.0082163. eCollection 2013.