PT  - JOURNAL ARTICLE
AU  - Carmona-Hidalgo, Beatriz
AU  - González-Mariscal, Isabel
AU  - García-Martín, Adela
AU  - Ruiz-Pino, Francisco
AU  - Appendino, Giovanni
AU  - Tena-Sempere, Manuel
AU  - Muñoz, Eduardo
TI  - Δ<sup>9</sup>-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in murine models of chemically- and obesity-induced liver injury
AID  - 10.1101/2020.05.11.088070
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.11.088070
4099  - http://biorxiv.org/content/early/2020/05/12/2020.05.11.088070.short
4100  - http://biorxiv.org/content/early/2020/05/12/2020.05.11.088070.full
AB  - Background Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Hepatocellular stellate cells (HSCs) activation by oxidative stress and inflammation is the hallmark of liver fibrosis and leads to cirrhosis and liver failure resistant to pharmacological management. Cannabinoids have been suggested as a potential therapy for liver fibrosis, prompting us to explore the antifibrotic and anti-inflammatory effects of Δ9-THCA-A, a major non-psychotropic cannabinoid from Cannabis sativa L., in animal models of NAFLD.Methods Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose and plasma insulin, leptin and triglyceride levels were measured in HFD mice.Results Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration.Conclusions Δ9-THCA prevents liver fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the treatment of liver fibrosis and the management of NAFLD.Competing Interest StatementThe authors have declared no competing interest.ALTAlanine aminotransferaseBWBody weightCB1RCannabinoid type 1 receptorCCl4Carbon tetrachlorideCDControl dietCLDChronic liver diseaseCLSCrown-like structuresDIODiet-induced obesityESLDEnd-stage liver diseaseGTTGlucose tolerance testHFDHigh fat dietHSCsHepatocellular stellate cellsiWATInguinal white adipose tissueLBDLigand binding domainMetSMetabolic syndromeNAFLDNon-alcoholic liver diseaseNASHSteatohepatitisPPARPeroxisome Proliferator-Activated ReceptorPSRPicrosirius redTGTriglycerideΔ9-THCΔ9-tetrahydrocannabinolΔ9-THCAΔ9-tetrahydrocannabinol acid.