PMID- 33341026 OWN - NLM STAT- MEDLINE DCOM- 20210224 LR - 20210224 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 81 DP - 2021 Jan TI - Delta9-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in mice. PG - 153426 LID - S0944-7113(20)30257-9 [pii] LID - 10.1016/j.phymed.2020.153426 [doi] 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. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. HYPOTHESIS: Delta(9)-tetrahydrocannabinolic acid (Delta(9)-THCA), the non-psychotropic precursor of Delta(9)-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Delta(9)-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. STUDY DESIGN: The antifibrotic activity of Delta(9)-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl(4) treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Delta(9)-THCA was administered daily intraperitoneally during the CCl(4) treatment or during the last 3 weeks in HFD-fed mice. METHODS: TGFbeta-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. RESULTS: Delta(9)-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFbeta in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Delta(9)-THCA significantly attenuated CCl(4)-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. Delta(9)-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. CONCLUSIONS: Delta(9)-THCA prevents TGFbeta-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD. CI - Copyright (c) 2020. Published by Elsevier GmbH. FAU - Carmona-Hidalgo, Beatriz AU - Carmona-Hidalgo B AD - Emerald Health Biotechnology, Astronoma Cecilia Payne (ed Centauro) s/n. floor 1. 14014. Cordoba, Spain. FAU - Gonzalez-Mariscal, Isabel AU - Gonzalez-Mariscal I AD - Biomedical Research Institute of Malaga (IBIMA), UGC Endocrinology and Nutrition. Regional Hospital of Malaga, Hospital Civil s/n. 29009. Malaga, Spain. FAU - Garcia-Martin, Adela AU - Garcia-Martin A AD - Emerald Health Biotechnology, Astronoma Cecilia Payne (ed Centauro) s/n. floor 1. 14014. Cordoba, Spain. FAU - Prados, Maria E AU - Prados ME AD - Emerald Health Biotechnology, Astronoma Cecilia Payne (ed Centauro) s/n. floor 1. 14014. Cordoba, Spain. FAU - Ruiz-Pino, Francisco AU - Ruiz-Pino F AD - Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Menendez Pidal s/n. 14004. Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Campus de Rabanales, Ctra. Madrid-Cadiz, Km. 396. 14071. Cordoba, Spain; University Hospital Reina Sofia, Menendez Pidal s/n. 14004. Cordoba, Spain. FAU - Appendino, Giovanni AU - Appendino G AD - Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani, 2. 28100. Novara, Italy. FAU - Tena-Sempere, Manuel AU - Tena-Sempere M AD - Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Menendez Pidal s/n. 14004. Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Campus de Rabanales, Ctra. Madrid-Cadiz, Km. 396. 14071. Cordoba, Spain; University Hospital Reina Sofia, Menendez Pidal s/n. 14004. Cordoba, Spain; CIBER Pathophysiology of Obesity and Nutrition, Carlos III Health Institute, Menendez Pidal s/n. 14004. Cordoba, Spain. FAU - Munoz, Eduardo AU - Munoz E AD - Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Menendez Pidal s/n. 14004. Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Campus de Rabanales, Ctra. Madrid-Cadiz, Km. 396. 14071. Cordoba, Spain; University Hospital Reina Sofia, Menendez Pidal s/n. 14004. Cordoba, Spain. Electronic address: fi1muble@uco.es. LA - eng PT - Journal Article DEP - 20201130 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 7J8897W37S (Dronabinol) RN - CL2T97X0V0 (Carbon Tetrachloride) SB - IM MH - Animals MH - Cannabis/chemistry MH - Carbon Tetrachloride/toxicity MH - Diet, High-Fat/adverse effects MH - Dronabinol/*pharmacology MH - Gene Expression Regulation/drug effects MH - Hepatitis/*drug therapy/etiology/pathology MH - Liver Cirrhosis/chemically induced/pathology/*prevention & control MH - Male MH - Mice MH - Mice, Inbred C57BL MH - NIH 3T3 Cells MH - Non-alcoholic Fatty Liver Disease/*drug therapy/etiology MH - Obesity/complications/etiology OTO - NOTNLM OT - Fibrogenesis OT - Inflammation OT - Liver OT - NAFLD OT - Delta(9)-THCA EDAT- 2020/12/20 06:00 MHDA- 2021/02/25 06:00 CRDT- 2020/12/19 20:15 PHST- 2020/06/13 00:00 [received] PHST- 2020/10/26 00:00 [revised] PHST- 2020/11/27 00:00 [accepted] PHST- 2020/12/20 06:00 [pubmed] PHST- 2021/02/25 06:00 [medline] PHST- 2020/12/19 20:15 [entrez] AID - S0944-7113(20)30257-9 [pii] AID - 10.1016/j.phymed.2020.153426 [doi] PST - ppublish SO - Phytomedicine. 2021 Jan;81:153426. doi: 10.1016/j.phymed.2020.153426. Epub 2020 Nov 30.