Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors’ Expression in Cultured HepaRG Cells

Abstract

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors’ expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.

The Role of Cannabidiol in Liver Disease: A Systemic Review

“…This study confirms that inhibiting CB1 receptors can improve lipid synthesis in an MASLD model [69]. Exosomes produced by hepatocytes during lipotoxic injury play a role in the pathogenesis of MASLD, and plasma-derived exosomes from MASLD patients are carriers of CB1R transport, capable of regulating CB1 receptor expression in HepaRG cells [70]. Meanwhile, in Kupffer cells of mice fed HFD deficient in methionine choline, the expression of CB1 increases and is closely associated with the expression of the NLRP3 inflammasome [71].…”