Hepatocyte steatosis activates macrophage inflammatory response accelerating atherosclerosis development.
10.3724/zdxbyxb-2023-0315
- Author:
Yue LI
1
;
Xize WU
2
;
Jiaxiang PAN
3
;
Lihong GONG
4
;
Dongyu MIN
5
Author Information
1. Department of Cardiology, the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China. med_liyue@163.com.
2. Department of Critical Care Medicine, Nantong Hospital of Traditional Chinese Medicine, Nantong 226000, Jiangsu Province, China.
3. Department of Cardiology, the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China.
4. Department of Cardiology, the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China. linda1795@sina.com.
5. Experimental Center of Traditional Chinese Medicine, the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China. mindongyu@163.com.
- Publication Type:Journal Article
- Keywords:
Atherosclerosis;
Cell experiment;
Comobidity;
Hepatic steatosis;
Inflammation;
Macrophage;
Network pharmacology;
Nonalcoholic fatty liver disease;
Untargeted metabolomics
- MeSH:
Animals;
Mice;
Non-alcoholic Fatty Liver Disease/metabolism*;
Cyclooxygenase 2/metabolism*;
PPAR gamma/metabolism*;
Reactive Oxygen Species/metabolism*;
Mice, Inbred C57BL;
Hepatocytes;
Macrophages/metabolism*;
Liver
- From:
Journal of Zhejiang University. Medical sciences
2023;52(6):751-765
- CountryChina
- Language:English
-
Abstract:
OBJECTIVES:To investigate the mechanism of comorbidity between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (AS) based on metabolomics and network pharmacology.
METHODS:Six ApoE－/－ mice were fed with a high-fat diet for 16 weeks as a comorbid model of NAFLD and AS (model group). Normal diet was given to 6 wildtype C57BL/6J mice (control group). Serum samples were taken from both groups for a non-targeted metabolomics assay to identify differential metabolites. Network pharmacology was applied to explore the possible mechanistic effects of differential metabolites on AS and NAFLD. An in vitro comorbid cell model was constructed using NCTC1469 cells and RAW264.7 macrophage. Cellular lipid accumulation, cell viability, morphology and function of mitochondria were detected with oil red O staining, CCK-8 assay, transmission electron microscopy and JC-1 staining, respectively.
RESULTS:A total of 85 differential metabolites associated with comorbidity of NAFLD and AS were identified. The top 20 differential metabolites were subjected to network pharmacology analysis, which showed that the core targets of differential metabolites related to AS and NAFLD were STAT3, EGFR, MAPK14, PPARG, NFKB1, PTGS2, ESR1, PPARA, PTPN1 and SCD. The Kyoto Encyclopedia of Genes and Genomes showed the top 10 signaling pathways were PPAR signaling pathway, AGE-RAGE signaling pathway in diabetic complications, alcoholic liver disease, prolactin signaling pathway, insulin resistance, TNF signaling pathway, hepatitis B, the relax in signaling pathway, IL-17 signaling pathway and NAFLD. Experimental validation showed that lipid metabolism-related genes PPARG, PPARA, PTPN1, and SCD were significantly changed in hepatocyte models, and steatotic hepatocytes affected the expression of macrophage inflammation-related genes STAT3, NFKB1 and PTGS2; steatotic hepatocytes promoted the formation of foam cells and exacerbated the accumulation of lipids in foam cells; the disrupted morphology, impaired function, and increased reactive oxygen species production were observed in steatotic hepatocyte mitochondria, while the formation of foam cells aggravated mitochondrial damage.
CONCLUSIONS:Abnormal lipid metabolism and inflammatory response are distinctive features of comorbid AS and NAFLD. Hepatocyte steatosis causes mitochondrial damage, which leads to mitochondrial dysfunction, increased reactive oxygen species and activation of macrophage inflammatory response, resulting in the acceleration of AS development.
