Garlic-derived exosomes regulate PFKFB3 expression to relieve liver dysfunction in high-fat diet-fed mice via macrophage-hepatocyte crosstalk

Jinfan Liu; Weizhao Li; Yangping Bian; Xiaoqing Jiang; Fuyun Zhu; Fei Yin; Li Yin; Xiaomei Song; Hong Guo; Jianhui Liu

doi:10.1016/j.phymed.2023.154679

Garlic-derived exosomes regulate PFKFB3 expression to relieve liver dysfunction in high-fat diet-fed mice via macrophage-hepatocyte crosstalk

Phytomedicine. 2023 Apr:112:154679. doi: 10.1016/j.phymed.2023.154679. Epub 2023 Jan 29.

Authors

Jinfan Liu¹, Weizhao Li¹, Yangping Bian¹, Xiaoqing Jiang¹, Fuyun Zhu¹, Fei Yin², Li Yin¹, Xiaomei Song³, Hong Guo⁴, Jianhui Liu⁵

Affiliations

¹ Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China; College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
² Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China; College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. Electronic address: fyin@cqut.edu.cn.
³ Department of Gastroenterology, Chongqing General Hospital, University of Chinese Academy of Sciences, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China.
⁴ Department of Gastroenterology, Chongqing General Hospital, University of Chinese Academy of Sciences, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China. Electronic address: hguo2013@aliyun.com.
⁵ Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing University of Technology, Chongqing 400054, China; College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. Electronic address: jhliu@cqut.edu.cn.

PMID: 36791628
DOI: 10.1016/j.phymed.2023.154679

Abstract

Background: Although macrophage-mediated low-grade chronic inflammation and liver dysfunction have been found to be associated with the development of non-alcoholic fatty (NAFLD) and widely reported, but strategies and drugs targeting macrophages for the treatment of NAFLD are limited.

Hypothesis/purpose: Garlic-derived exosomes (GDE) can be useful for NAFLD due to its anti-inflammatory activity. Clarify whether GDE improves liver dysfunction through macrophage-hepatocyte crosstalk.

Methods: GDE was isolated with PEG precipitation and ultracentrifuge. Inflammatory cytokines were detected by qRT-PCR and ELISA. Expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) was determined using qRT-PCR and western blot. Crosstalk between macrophages and hepatocytes was identified through a co-culture experiment. Small RNA sequencing and bioinformatic analysis were used to identify the key element of GDE regulating the expression of PFKFB3 gene.

Results: GDE regulated the expression of PFKFB3 to reduce the inflammatory response in LPS-treated differentiated THP-1 macrophages. Data from small RNA sequencing and bioinformatics analysis reveal that miR-396e, one of the most abundant miRNAs of GDE, is the key component to regulate PFKFB3 expression. Mechanistically, miR-396e-mediating PFKFB3 expression plays a crucial role in GDE inhibiting inflammatory response and enhancing lipid metabolism in hepatocytes via the macrophage-hepatocyte crosstalk. Notably, GDE supplementation reduced the inflammatory response and improved liver dysfunction in high-fat diet-fed mice.

Conclusion: GDE may be useful for improving the symptoms of NAFLD via macrophage-hepatocyte crosstalk and its role in PFKFB3 expression.

Keywords: Garlic-derived exosomes (GDE); Inflammation; Lipid metabolism; Nonalcoholic fatty liver disease (NAFLD); Phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3).

MeSH terms

Animals
Diet, High-Fat
Exosomes* / metabolism
Garlic*
Hepatocytes / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL
MicroRNAs* / metabolism
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

MicroRNAs