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

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.

Garlic-derived exosomes carrying miR-396e shapes macrophage metabolic reprograming to mitigate the inflammatory response in obese adipose tissue.

Low-grade chronic inflammation originating from the adipose tissue and imbalance of lipid metabolism in the liver are the main drivers of the development of obesity and its related metabolic disorders. In this work, we found that garlic-derived exosomes (GDE) supplementation improved insulin resistance, altered the levels of inflammatory cytokines in serum and epididymal white adipose tissue (eWAT) by decreasing the accumulation of macrophages in HFD-fed mice. Meanwhile, we also observed that GDE regulated the expression of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), one of the critical glycolytic enzymes, to shape the metabolic reprograming of macrophage induced by lipopolysaccharide (LPS) and mitigate the inflammatory response in adipocytes via macrophage-adipocyte cross-talk. Data from small RNA sequencing, bioinformatical analysis and the gene over-expression revealed that miR-396e, one of the most abundant miRNAs of GDE, played a critical role in promoting the metabolic reprogramming of macrophage by directly targeting PFKFB3. The findings of this study not only provide an in-depth understanding of GDE protecting against inflammation in obesity but supply evidence to study the molecular mechanisms associated with the interspecies communication.