Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans

PLoS One. 2013 Dec 11;8(12):e82163. doi: 10.1371/journal.pone.0082163. eCollection 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Clodronic Acid / pharmacology
  • Fatty Liver / pathology*
  • Female
  • Hepatitis, Viral, Human / pathology
  • Humans
  • Inflammation / pathology
  • Lipid Metabolism / drug effects
  • Liposomes / metabolism
  • Liver / drug effects
  • Liver / pathology*
  • Liver / ultrastructure
  • Liver Cirrhosis / pathology
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Phenotype
  • Receptor, Melanocortin, Type 4 / metabolism


  • Liposomes
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4
  • Clodronic Acid

Grant support

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Ministry of Health, Labour and Welfare of Japan, and Japan Science and Technology Agency, PRESTO. This work was also supported by research grants from Takeda Science Foundation, Ono Medical Research Foundation, Japan Research Foundation for Clinical Pharmacology, Nestlé Nutrition Council, Japan, Astellas Foundation for Research on Metabolic Disorders, The Uehara Memorial Foundation, and the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.