Immunomodulatory effects of non-psychoactive cannabinoids in a model of metabolic dysfunction-associated steatotic liver disease (MASLD) 2232983

Abstract Introduction Emerging evidence suggests that activation of different immune cell populations contributes to the progression of MASLD to advanced MASH. Thus, with lipogenic and fibrotic markers, exploring liver innate and adaptive immune cell activation and recruitment can enhance understanding of MASLD progression and therapeutic targets. Previous studies showed CBG, a non-psychotropic cannabinoid, reduces inflammation in MCD diet-induced MASH, while CBD alleviates alcohol-induced liver steatosis. Considering this, the study explores the efficacy of CBG alone or with CBD in MASLD-associated inflammation and metabolic disorders. Methods In vivo, blood glucose levels, serum insulin, and adiponectin are analyzed. Inflammation by innate immune cells is assessed by IHC for CD45, CK19, F4/80 (Kupffer), and infiltrated macrophages—M1 and M2, and LPS-induced IL-6 production from isolated hepatocytes. Adaptive immunomodulation is assessed by T cell numbers (CD4+ and CD8+) +/- the treatments in peripheral blood, spleen, and liver. In vitro, steatosis is induced in hepatocytes by free fatty acid, followed by CBG or CBD to evaluate effects on fat accumulation. Results In vivo, CBG decreases Kupffer cells, M1 macrophages, and ductular proliferation, but increases M2 macrophages in both sexes. It also improves steatosis, increases adiponectin, and lowers insulin. In vitro, CBG decreases fat accumulation, while the combo reduces IL-6. Conclusion Together these data suggest a promising therapeutic potential of CBG in MASLD. Funding Source National Institute of Health (NIH), [Grant number: 1R15DK131507-01A1] Topic Categories Immune Mechanisms of Human Disease (HUM)