Background: Non-alcoholic fatty liver disease (NAFLD) constitutes a global pandemic. An intricate network among cytokines and lipids possesses a central role in NAFLD pathogenesis. Red blood cells comprise an important source of both cytokines and signaling lipids and have an important role in molecular crosstalk during immunometabolic deregulation. However, their role in NAFLD has not been thoroughly investigated. Methods: Conditioned media from erythrocytes derived from 10 NAFLD patients (4 men, 6 women, aged 57.875±15.16) and 10 healthy controls (4 men, 6 women, aged 39.3±15.55) was analyzed for the cytokines IFN-γ, TNF-α, CCL2, CCL5, IL-8, IL-1β, IL-12p40, IL-17, MIP-1β, the signaling lipids sphingosine-1phosphate (S1P) and lysophosphatidic acid (LPA), and cholesterol. Their effect on the cytokine profile released by RAW 264.7 macrophages was also studied. Results: MCP1 levels were greater in conditioned growth medium from NAFLD patient erythrocytes than in that from healthy controls (37±40 vs 6.51±5.63 pg/ml). No statistically significant differences were found between patients and healthy controls with regard to S1P, LPA, cholesterol, or eight other cytokines. TNFa release by RAW 264.7 cells was greater after incubation with patient-derived erythrocyte-conditioned medium than in medium without RAW 264.7 cells from either healthy or NAFLD subjects. Conclusions: Erythrocytes may contribute to liver infiltration by monocytes, and macrophage activation, partially due to CCL2 release, in the context of NAFLD.
BACKGROUND: Non-Alcoholic Fatty Liver Disease (NAFLD) constitutes a global pandemic. An intricate network among cytokines and lipids possesses a central role in NAFLD pathogenesis. Red blood cells comprise an important source of both cytokines and signaling lipids and have an important role in the molecular crosstalk during immunometabolic deregulation. However, their role in NAFLD has not been investigated in deep.
METHODS: Conditioned media from erythrocytes derived from 10 NAFLD patients (4 men, 6 women, aged 57.875+-15,16) and 10 healthy controls (4 men, 6 women, aged 39.3+-15.55) were produced and used for the analysis of 9 cytokines (IFN-γ, TNF-α, CCL2, CCL5, IL-8, IL-1β, IL-12p40, IL-17, MIP-1β), 2 signaling lipids (Sphingosine 1-phosphate and Lysophosphatidic Acid), and cholesterol. Their effect on the cytokine profile released by RAW 264.7 macrophages was also studied.
RESULTS: Erythrocytes from patients with NAFLD augmented the levels of MCP1 in the growth medium in comparison to the erythrocytes derived from healthy controls (37+-40 pg/ml vs 6.51+-5.63). No statistically significant differences were found between patients and healthy controls with regard to S1P, LPA, cholesterol and 8 other cytokines. TNF-a release by RAW 264.7 cells was increased after incubation with patient-derived erythrocyte conditioned medium compared to medium without RAW 264.7 cells from either healthy of NAFLD subjects.
CONCLUSIONS: Erythrocytes could contribute to the liver infiltration by monocytes and to the activation of macrophages, partially due to release of CCL2, in the context of NAFLD.
Non-alcoholic liver disease (NAFLD) constitutes a global health pandemic. It is estimated that about 25% of the world’s population suffers from NAFLD. In the long-term, a subgroup of the patients can develop inflammation and fibrosis. The end result in some cases is cirrhosis and even liver-related death. The epidemiology and natural history of NAFLD lead to extreme financial costs.
To date, there is no approved treatment for NAFLD. Lipotoxicity has been proposed to be one of the main regulators of the implicated molecular pathomechanisms. Research has been focused on the role of cholesterol, free fatty acids and ceramides. Nevertheless, lysophospholipids, such as sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) have emerged as potential contributors to NAFLD/NASH. Finally, the metabolism of other lysophospholipids, such as lysophosphatidylserine (LPSer), lysophosphatidylglycerol (LPG), and lysocardiolipin (LCL), has come to light in the context of NAFLD. In this review, we try to summarize the current knowledge regarding the potential of lysophospholipid signalling and metabolism as therapeutic targets and biomarkers in NAFLD and/or NASH.
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