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Published on: April 26, 2019
Phenotypic Changes in Macrophage Activation in a Model of Nonalcoholic Fatty Liver Disease using Microminipigs
Daiki Yoshii1, Takenobu Nakagawa1, Yoshihiro Komohara1,2
1Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University.
Aim:
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders associated with metabolic syndrome, and its prevalence has been on the rise. The pathogenesis of NAFLD has not yet been sufficiently elucidated due to the multifactorial nature of the disease, although the activation of macrophages/Kupffer cells is considered to be involved. We previously reported an animal model of NAFLD using MicrominipigsTM (µMPs) fed high-fat diets containing cholesterol with or without cholic acid. The aim of this study was to investigate the phenotypic changes of macrophages that occur during the development of NAFLD.
Methods:
Immunohistochemistry of macrophages, lymphocytes, and stellate cells was performed using liver samples, and the density of positive cells was analyzed.
Results:
The number of Iba-1-positive macrophages increased with increasing cholesterol content in the diet. The numbers of CD163-positive macrophages and CD204-positive macrophages also increased with increasing cholesterol content in the diet; however, the proportion of CD204-positive macrophages among Iba-1-positive macrophages was significantly reduced by cholic acid supplementation.
Conclusion:
The results suggest that lipid accumulation induced macrophage recruitment in swine livers, and that the number of M2-like macrophages increased at the early stage of NAFLD, while the number of M1-like macrophages increased at the late stage of NAFLD, resulting in a liver condition like non-alcoholic steatohepatitis. We provide evidence of the phenotypic changes that occur in macrophages during the development of NAFLD that has never been reported before using µMPs.
Insights
Lipid accumulation in swine livers drives macrophage changes during non-alcoholic fatty liver disease (NAFLD) development. M2-like macrophages increase early, followed by M1-like macrophages, potentially leading to non-alcoholic steatohepatitis.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern linked to metabolic syndrome.
- The precise mechanisms driving NAFLD pathogenesis remain unclear, but macrophage activation is implicated.
- A Microminipigs (µMPs) model of NAFLD was previously established using high-fat diets.
Purpose of the Study:
- To investigate the phenotypic alterations of macrophages during NAFLD progression in a swine model.
- To elucidate the role of dietary cholesterol and cholic acid in modulating macrophage populations in NAFLD.
Main Methods:
- Immunohistochemistry was employed to analyze liver samples from µMPs.
- The density of macrophages (Iba-1+), M2-like macrophages (CD163+), and M1-like macrophages (CD204+) was quantified.
- Stellate cells and lymphocytes were also assessed.
Main Results:
- Increased dietary cholesterol correlated with a higher number of Iba-1-positive macrophages.
- Both CD163-positive and CD204-positive macrophage populations increased with dietary cholesterol.
- Cholic acid supplementation reduced the proportion of CD204-positive macrophages relative to total macrophages.
Conclusions:
- Dietary lipids promote macrophage recruitment in swine livers, a key event in NAFLD development.
- A shift towards M2-like macrophages occurs in early NAFLD, followed by an increase in M1-like macrophages in later stages.
- These findings provide novel insights into macrophage phenotypic changes during NAFLD progression in the µMPs model.
