Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease.

Alcohol Res. 2021;41(1):12 | https://doi.org/10.35946/arcr.v41.1.12 Published: 23 September 2021 Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease Keungmo Yang,1 Sung Eun Choi,1 and Won-Il Jeong1,2 Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea 2 Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea 1 Correspondence Address correspondence concerning this article to Won-Il Jeong, D.V.M., Ph.D., Laboratory of Liver Research, Building E7, Room 8107, GSMSE/KAIST, 291 Daehakro, Yuseong-gu, Daejeon 34141, Republic of Korea. Email: Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government Ministry of Science and Information and Communications Technology (2018R1A2A1A05077608 and 2021R1A3B1076878); Global Ph.D. Fellowship Program (NRF2019H1A2A1074222); Korea Mouse Phenotyping Project (2014M3A9D5A01073556); and KAIST Grand Challenge 30 Project (N11210112). Disclosures The authors declare no competing financial or nonfinancial interests. Publisher’s Note Opinions expressed in contributed articles do not necessarily reflect the views of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. The U.S. government does not endorse or favor any specific commercial product or commodity. Any trade or proprietary names appearing in Alcohol Research: Current Reviews are used only because they are considered essential in the context of the studies reported herein. PURPOSE: The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD. SEARCH METHODS: Three electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were “cannabinoid,” “cannabinoid receptor,” “ALD,” “steatosis,” and “fibrosis.” SEARCH RESULTS: According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD. DISCUSSION AND CONCLUSIONS: This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD. KEYWORDS: alcohol; CB1R; CB2R; cell communication; endocannabinoid; fatty liver; metabotropic glutamate receptor 5; xCT The prevalence of alcohol use disorder has been steadily rising around the world in recent years, and reducing the burden of alcohol-associated liver disease (ALD) caused by chronic alcohol consumption has become one of the most important global health issues.1,2 Excessive alcohol drinking (more than 40 g of pure alcohol per day) is closely associated with increased risk of all-cause mortality including chronic diseases, such as cancer, cardiovascular conditions, and neuronal diseases.3 ALD comprises a wide spectrum of liver injury including simple steatosis, steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. The predominant cause of alcohol-associated liver disease, as evident by its name, is the persistent intake of alcohol, and yet the detailed mechanisms of ALD progression remain vague.4,5 ALD develops through complex signaling pathways in the liver.6 Chronic alcohol consumption not only elicits various responses by innate immune cells in the liver, but also contributes to the metabolic dysfunction of hepatocytes, such as the production of reactive oxygen species (ROS), the abnormal lipogenesis induced by endoplasmic reticulum stress or mitochondrial dysfunction, and the secretion of inflammatory cytokines.6 Apart from alcohol-induced effects, endogenous cannabinoids (endocannabinoids), which are lipid mediators, also were found to play an important role in provoking ethanolinduced hepatic steatosis.7 The study of endocannabinoids began with the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, binds to G-protein-coupled receptors and exhibits diverse biological effects in the brain depending on the types of functioning cells affected.8 Over the past 3 decades, mounting evidence has shown that in peripheral organs, endocannabinoids modulate the progression of various diseases including nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and ALD.9 However, the underlying mechanisms and the specifics of the cannabinoid signaling are yet to be elucidated. The authors of this review recently reported, however, that alcoholic steatosis is promoted by endocannabinoid production in hepatic stellate cells (HSCs), which is mediated by metabotropic glutamate receptor 5 (mGluR5).10 This review explores cannabinoid signaling in regard to the general physiology of hepatic function, the pathogenesis of ALD, and the potential therapeutic implications for ALD. search terms used were “cannabinoid,” “endocannabinoid,” “cannabinoid receptor,” “alcoholic liver disease,” “steatosis,” and “fibrosis.” Among the initial search results retrieved from the online databases, articles published later than April 2021 and duplicate articles were removed, and articles written in English were screened first. Then, the authors included peerreviewed original articles on animal experiments or clinical trials and well-organized review articles relevant to the subject. Research articles without peer review, abstracts of conferences or posters, and articles with unclear research processes or insufficient data were excluded. As a result, 47 eligible full-text articles were selected from a total of 2,691 searched initially. All authors independently conducted literature searches using the same online databases, and then selected appropriate references according to the inclusion and exclusion criteria. Cannabinoid Signaling Systems and Hepatic Function Endocannabinoid System Marijuana (Cannabis sativa) has been widely used for medical applications (e.g., analgesic, antiemetic, appetite stimulant) since its discovery in ancient times.11 Now it is better known (...truncated)