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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans
Michiko Itoh1, Hideaki Kato2, Takayoshi Suganami3
1Department of Organ Network and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan.
Insights
Researchers discovered hepatic crown-like structures (hCLS) in non-alcoholic steatohepatitis (NASH). These structures, formed by macrophages, are linked to liver inflammation and fibrosis, playing a key role in NASH progression.
Area of Science:
- Hepatology
- Immunology
- Pathology
Background:
- Macrophages are implicated in chronic inflammatory diseases.
- The role of macrophages in non-alcoholic fatty liver disease (NAFLD) progression to non-alcoholic steatohepatitis (NASH) remains unclear.
Purpose of the Study:
- To investigate the role of macrophages in the progression of simple steatosis to NASH.
- To identify novel histological structures associated with NASH pathogenesis.
Main Methods:
- Utilized a mouse model of NASH (melanocortin-4 receptor deficient mice on a Western diet).
- Performed histological analysis to identify and characterize hepatic crown-like structures (hCLS).
- Assessed the impact of macrophage depletion on hepatic gene expression and fibrosis.
Main Results:
- Identified unique "hepatic crown-like structures" (hCLS) composed of CD11c-positive macrophages surrounding lipid-laden hepatocytes.
- hCLS were associated with activated fibroblasts and collagen deposition, indicating fibrosis.
- Macrophage depletion in the liver, sparing hCLS, did not affect inflammatory or fibrogenic gene expression, suggesting hCLS as a source of these factors.
- The number of hCLS positively correlated with liver fibrosis extent.
- Increased hCLS were observed in human NASH patients.
Conclusions:
- Hepatic crown-like structures (hCLS) are a novel histological finding in NASH.
- hCLS are associated with hepatic inflammation and fibrosis, contributing to NASH progression.
- hCLS may represent a critical pathophysiological component in the transition from simple steatosis to NASH.
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.
