**8. Conclusions**

The EC and apelin systems are two of the multiple cell-signalling pathways involved in the pathogenesis of liver fibrosis. Both systems play a major role in the pathophysiological mechanisms underlying the control of HSC activity, involving different receptors and molecules, but with a common significant impact in the development of liver fibrosis.

The ECS is upregulated in liver disease and has been associated with hepatic steatosis, regeneration, fibrosis, and cirrhosis. In liver fibrosis, the cannabinoid receptors CB1 and CB2 exhibit opposite roles: CB1 activation accentuates hepatic fibrosis progression whereas CB2 displays anti-fibrogenic and anti-inflammatory activities. CB1 also contributes significantly to cirrhosis complications including portal hypertension, splanchnic vasodilation, cardiomyopathy, and encephalopathy. More specific CB1 antagonists and CB2 agonists need to be developed as current CB1 antagonists are able to cross the blood–brain barrier causing psychotic side effects. Compounds targeting EC synthesis, degradation, and cellular transport pathways could also be a valuable approach to modulate the ECS. Several efforts have been devoted to understanding the specific pathways regulated by this system but there is still a long way to go in the development of drugs targeting the ECS.

Recent studies have reported multiple roles for the apelin/APJ system in liver disease, including acute liver injury, regeneration, fibrosis progression, and cirrhosis. Apelin/APJ has unique functions as a regulator of cell proliferation, apoptosis, pro-inflammatory activity, and revascularization. Apelin/APJ gene expression is temporally increased during liver cirrhotic development and is decreased in stabilized liver fibrosis. The validation of using apelin/APJ as a biomarker in different liver diseases would also be a crucial step toward its clinical use. Further experimental or clinical findings will help to determine the potential of therapeutic strategies targeting the apelin/APJ system for the treatment of liver disease.

Future investigations to further define the mechanisms by which the EC and apelin systems contribute to modulate liver fibrosis will enhance our understanding of their cellular and molecular mechanisms and possible therapeutic targets. This understanding will eventually help in the development of novel therapeutic strategies and drug candidates for treating liver fibrosis in patients with chronic liver disease.

**Author Contributions:** Writing—review and editing, P.M.-L., M.P., and W.J.; P.M.-L. and M.P. composed the figures.

**Funding:** This work was supported by grants to W.J. and P.M.-L. from the Ministerio de Ciencia, Innovación y Universidades (grant RTI2018-094734-B-C21), and the AGAUR Beatriu de Pinos Program 2016 (BP-00236) and then from the Ramón y Cajal Program 2018 (Ministerio de Ciencia, Innovación y Universidades, Reference: RYC2018-023971-I) to P.M-L. The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III.

**Conflicts of Interest:** The authors declare no conflict of interest.
