Endocannabinoid signaling in liver pathologies

The endocannabinoid system (eCB) comprises a class of signaling lipids, their receptors, and associated turnover enzymes. Ongoing research is revealing complex intertwining with other pathways and a seemingly universal involvement of the eCB system in the tuning of cellular signaling. Moreover, derangement of the eCB system has been causally linked to an increasing number of pathologies. In liver, an elevated eCB tone participates all the way along the axis from steatosis to end-stage disease, with the canonical cannabinoid receptors CNR1 and CNR2 often acting in opposing ways. In preclinical models, CNR modulation not only mitigates fatty liver, inflammation or fibrosis, but exerts beneficial effects on cirrhosis and beyond. This extensive influence suggests that the CNRs may become key therapeutic targets in liver pathologies for which currently little treatment exists. Full appreciation of the subtleties behind hepatic eCB signaling will be the future challenge.