{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:36:15Z","timestamp":1783823775895,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Provost\u2019s Seed Grant and Dissemination and Faculty Development Program from University of Northern Colorado"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). NASH is distinguished by severe hepatic fibrosis and inflammation. The plant-derived, non-psychotropic compound cannabigerol (CBG) has potential anti-inflammatory effects similar to other cannabinoids. However, the impact of CBG on NASH pathology is still unknown. This study demonstrated the therapeutic potential of CBG in reducing hepatic steatosis, fibrosis, and inflammation. Methods: 8-week-old C57BL\/6 male mice were fed with methionine\/choline deficient (MCD) diet or control (CTR) diets for five weeks. At the beginning of week 4, mice were divided into three sub-groups and injected with either a vehicle, a low or high dose of CBG for two weeks. Overall health of the mice, Hepatic steatosis, fibrosis, and inflammation were evaluated. Results: Increased liver-to-body weight ratio was observed in mice fed with MCD diet, while a low dose of CBG treatment rescued the liver-to-body weight ratio. Hepatic ballooning and leukocyte infiltration were decreased in MCD mice with a low dose of CBG treatment, whereas the CBG treatment did not change the hepatic steatosis. The high dose CBG administration increased inflammation and fibrosis. Similarly, the expression of cannabinoid receptor (CB)1 and CB2 showed decreased expression with the low CBG dose but not with the high CBG dose intervention in the MCD group and were co-localized with mast cells. Additionally, the decreased mast cells were accompanied by decreased expression of transforming growth factor (TGF)-\u03b21. Conclusions: Collectively, the low dose of CBG alleviated hepatic fibrosis and inflammation in MCD-induced NASH, however, the high dose of CBG treatment showed enhanced liver damage when compared to MCD only group. These results will provide pre-clinical data to guide future intervention studies in humans addressing the potential uses of CBG for inflammatory liver pathologies, as well as open the door for further investigation into systemic inflammatory pathologies.<\/jats:p>","DOI":"10.3390\/nu15010178","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T02:23:06Z","timestamp":1672626186000},"page":"178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Low-Dose Administration of Cannabigerol Attenuates Inflammation and Fibrosis Associated with Methionine\/Choline Deficient Diet-Induced NASH Model via Modulation of Cannabinoid Receptor"],"prefix":"10.3390","volume":"15","author":[{"given":"Nouf","family":"Aljobaily","sequence":"first","affiliation":[{"name":"Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9588-6144","authenticated-orcid":false,"given":"Kelsey","family":"Krutsinger","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Viereckl","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raznin","family":"Joly","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8890-0115","authenticated-orcid":false,"given":"Bridger","family":"Menlove","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brexton","family":"Cone","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailaina","family":"Suppes","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-9286","authenticated-orcid":false,"given":"Yuyan","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","author":"Loomba","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/liv.13302","article-title":"Therapies in non-alcoholic steatohepatitis (NASH)","volume":"37","author":"Oseini","year":"2017","journal-title":"Liver Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"154822","DOI":"10.1016\/j.metabol.2021.154822","article-title":"Preparing for the NASH epidemic: A call to action","volume":"122","author":"Kanwal","year":"2021","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcome","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e042843","DOI":"10.1136\/bmjopen-2020-042843","article-title":"Increasing prevalence of NAFLD\/NASH among children, adolescents and young adults from 1990 to 2017: A population-based observational study","volume":"11","author":"Zhang","year":"2021","journal-title":"BMJ Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.3748\/wjg.v20.i10.2515","article-title":"Hepatic inflammation and progressive liver fibrosis in chronic liver disease","volume":"20","author":"Czaja","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/labinvest.2009.123","article-title":"Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine\u2013choline-deficient diet","volume":"90","author":"Mu","year":"2010","journal-title":"Lab Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.jhep.2020.03.011","article-title":"Hepatic fibrosis: A convergent response to liver injury that is reversible","volume":"73","author":"Wang","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_9","first-page":"40","article-title":"Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail","volume":"9","author":"Sharma","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and future pharmacological therapies for NAFLD\/NASH","volume":"53","author":"Sumida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/TP.0000000000002485","article-title":"Management of Recurrent and De Novo NAFLD\/NASH After Liver Transplantation","volume":"103","author":"Germani","year":"2019","journal-title":"Transplantation"},{"key":"ref_12","unstructured":"American Liver Foundation (2021, November 21). NASH Clinical Trial Overview and Trial Finder. American Liver Foundation. Published 2021. Available online: https:\/\/liverfoundation.org\/for-patients\/resources\/nonalcoholic-steatohepatitis-nash-clinical-trials\/."},{"key":"ref_13","unstructured":"Mayo Foundation for Medical Education and Research (2021, November 21). Nonalcoholic Steatohepatitis (NASH) Clinical Trials\u2014Mayo Clinic Research. Available online: https:\/\/www.mayo.edu\/research\/clinical-trials\/diseases-conditions\/nonalcoholic-steatohepatitis-(nash)."},{"key":"ref_14","unstructured":"National Cancer Institute (NCI) (2021, November 18). Role of Lisinopril in Preventing the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD): Relief-NAFLD; clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04550481."},{"key":"ref_15","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2021, November 18). Treatment of Nonalcoholic Steatohepatitis With Metformin; clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00063232."},{"key":"ref_16","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2021, November 18). Vitamin E Pharmacokinetics and Biomarkers in Normal and Obese Women; clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00862433."},{"key":"ref_17","first-page":"e20210030","article-title":"Current considerations for clinical management and care of non-alcoholic fatty liver disease: Insights from the 1st International Workshop of the Canadian NASH Network (CanNASH)","volume":"5","author":"Sebastiani","year":"2021","journal-title":"Can Liver J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/j.bcp.2013.01.017","article-title":"Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease","volume":"85","author":"Borrelli","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.tips.2006.01.010","article-title":"A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the work of British scientists","volume":"27","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12064","DOI":"10.1038\/s41598-017-10924-8","article-title":"Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.euroneuro.2017.03.006","article-title":"The acute effect of cannabis on plasma, liver and brain ammonia dynamics, a translational study","volume":"27","author":"Abulseoud","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fendo.2020.00103","article-title":"The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease","volume":"11","author":"Lara","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21224","DOI":"10.1002\/jcp.28728","article-title":"Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-\u03baB and NLRP3 inflammasome pathway","volume":"234","author":"Huang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41401-019-0210-3","article-title":"Cannabis, cannabinoid receptors, and endocannabinoid system: Yesterday, today, and tomorrow","volume":"40","author":"Wu","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1172\/JCI34827","article-title":"Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice","volume":"118","author":"Liu","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/hep.24077","article-title":"Endocannabinoids in liver disease","volume":"53","author":"Tam","year":"2011","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1478-3231.2007.01483.x","article-title":"Current concepts in the pathogenesis of nonalcoholic fatty liver disease","volume":"27","author":"Arrese","year":"2007","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/cld.527","article-title":"Cannabinoids in liver diseases: Endocannabinoids and Liver","volume":"7","author":"Patsenker","year":"2016","journal-title":"Clin. Liver Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Machado, M.V., Michelotti, G.A., Xie, G., de Almeida, T.P., Boursier, J., Bohnic, B., Guy, C.D., and Diehl, A.M. (2015). Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132315"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/path.4829","article-title":"Animal models of non-alcoholic fatty liver disease: Current perspectives and recent advances: NAFLD animal models","volume":"241","author":"Lau","year":"2017","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.3748\/wjg.v18.i19.2300","article-title":"Animal models of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"18","author":"Takahashi","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ptr.4966","article-title":"Animal studies on medicinal herbs: Predictability, dose conversion and potential value","volume":"28","author":"Wojcikowski","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20405","DOI":"10.1038\/s41598-020-77175-y","article-title":"In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa","volume":"10","author":"Zagzoog","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1136\/gut.2010.222844","article-title":"Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C","volume":"60","author":"Ochoa","year":"2011","journal-title":"Gut"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41419-020-03003-w","article-title":"Understanding lipotoxicity in NAFLD pathogenesis: Is CD36 a key driver?","volume":"11","author":"Rada","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_36","first-page":"715","article-title":"The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women","volume":"7","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis","volume":"158","author":"Schwabe","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1002\/hep.26783","article-title":"Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C+ macrophage infiltration in mice","volume":"59","author":"Baeck","year":"2014","journal-title":"Hepatology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"632","DOI":"10.3389\/fphar.2018.00632","article-title":"Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1\u2013CB2 Heteroreceptor Complexes","volume":"9","author":"Navarro","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1476-5381.2009.00515.x","article-title":"Evidence that the plant cannabinoid cannabigerol is a highly potent \u03b12-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist: Novel pharmacological actions of cannabigerol","volume":"159","author":"Cascio","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1042\/BJ20041682","article-title":"Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells","volume":"388","author":"Shimoda","year":"2005","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3389\/fimmu.2012.00119","article-title":"Mast Cell Chemotaxis\u2014Chemoattractants and Signaling Pathways","volume":"3","author":"Halova","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/liv.14869","article-title":"Current management of NAFLD\/NASH","volume":"41","author":"Cardoso","year":"2021","journal-title":"Liver Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/s12944-017-0572-9","article-title":"A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease","volume":"16","author":"Chen","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"16210","DOI":"10.1038\/s41598-019-52736-y","article-title":"Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis","volume":"9","author":"Ganbold","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jhep.2003.09.020","article-title":"The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance","volume":"40","author":"Rinella","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3727\/105221617X15093707969658","article-title":"Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights","volume":"18","author":"Stephenson","year":"2018","journal-title":"Gene Expr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"858","DOI":"10.3389\/fmicb.2020.00858","article-title":"Cannabigerol Prevents Quorum Sensing and Biofilm Formation of Vibrio harveyi","volume":"11","author":"Aqawi","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_50","unstructured":"Jazz Pharmaceuticals (2022, September 26). A Randomised, Partially-Blind, Placebo-Controlled, Pilot, Dose-Ranging Study To Assess The Effect Of Cannabidiol (CBD) On Liver Fat Levels In Subjects With Fatty Liver Disease; clinicaltrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01284634."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhou, X., Yang, L., Fan, X., Zhao, X., Chang, N., Yang, L., and Li, L. (2020). Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1\/G\u03b1i\/o\/ROS\/p38 MAPK Signaling Pathway. Cells, 9.","DOI":"10.3390\/cells9020373"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1172\/JCI200523057","article-title":"Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity","volume":"115","author":"DePetrillo","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"R345","DOI":"10.1152\/ajpregu.00545.2002","article-title":"Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice","volume":"284","author":"Arnone","year":"2003","journal-title":"Am. J. Physiol-Regul. Integr. Comp. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1002\/hep.31497","article-title":"Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell\u2013Derived Transforming Growth Factor Beta 1 Signaling","volume":"73","author":"Kyritsi","year":"2021","journal-title":"Hepatology"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/1\/178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:56:23Z","timestamp":1760147783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/1\/178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,30]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["nu15010178"],"URL":"https:\/\/doi.org\/10.3390\/nu15010178","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,30]]}}}