Research progress in the role of endo cannabinoid system in liver diseases

doi:10.3969/j.issn.1674-8115.2024.10.012

Abstract

Abstract:

The endocannabinoid system (ECS) consists of a variety of long-chain unsaturated fatty acid analogs, mainly anandamide (AEA) and 2-arachidoniyl glycerol (2-AG), along with their specific binding G protein-coupled receptors, cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). It affects the life process and biological activity of almost all cells in the body by influencing cell material and energy metabolism. In the liver, the physiological expression of ECS is at a low level. The expression and secretion of ECS in the liver can be strongly stimulated by liver injury factors. ECS acts as a trigger in multiple liver diseases. It is known to be related to the process of hepatocyte steatosis and promote the formation and development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). It is involved in the inflammatory processes of liver diseases and greatly affects the immune-inflammatory response in liver tissue. It is also involved in the formation of liver fibers and promotes the occurrence and development of liver fibrosis and cirrhosis. Finally, the role and mechanisms of ECS in the occurrence and development of liver diseases are elaborated in detail by listing lipid metabolism-related liver diseases (NAFLD and ALD) and other liver diseases.

Key words: endocannabinoid system (ECS), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), liver injury, hepatic fibrosis

CLC Number:

R575.5

BIAN Shu, YU Qian, LIU Liangming. Research progress in the role of endo cannabinoid system in liver diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1299-1306.

Figures/Tables 2

TrendMD

References 48

1	AMADIO D, FEZZA F, CATANZARO G, et al. Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system[J]. Biochimie, 2010, 92(4): 378-387.
2	BLANKMAN J L, SIMON G M, CRAVATT B F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol[J]. Chem Biol, 2007, 14(12): 1347-1356.
3	SANG N, ZHANG J, CHEN C. PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons[J]. J Physiol, 2006, 572(Pt 3): 735-745.
4	DE GOTTARDI A, SPAHR L, RAVIER-DALL'ANTONIA F, et al. Cannabinoid receptor 1 and 2 agonists increase lipid accumulation in hepatocytes[J]. Liver Int, 2010, 30(10): 1482-1489.
5	LOUVET A, TEIXEIRA-CLERC F, CHOBERT M N, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice[J]. Hepatology, 2011, 54(4): 1217-1226.
6	COOPMAN K, SMITH L D, WRIGHT K L, et al. Temporal variation in CB2R levels following T lymphocyte activation: evidence that cannabinoids modulate CXCL12-induced chemotaxis[J]. Int Immunopharmacol, 2007, 7(3): 360-371.
7	MALLAT A, TEIXEIRA-CLERC F, DEVEAUX V, et al. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings[J]. Br J Pharmacol, 2011, 163(7): 1432-1440.
8	LIU Q R, CANSECO-ALBA A, LIANG Y, et al. Low basal CB2R in dopamine neurons and microglia influences cannabinoid tetrad effects[J]. Int J Mol Sci, 2020, 21(24): 9763.
9	ZELBER-SAGI S, AZAR S, NEMIROVSKI A, et al. Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease[J]. Obesity, 2017, 25(1): 94-101.
10	BLÜHER M, ENGELI S, KLÖTING N, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity[J]. Diabetes, 2006, 55(11): 3053-3060.
11	MULLER T, DEMIZIEUX L, TROY-FIORAMONTI S, et al. Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue[J]. Am J Physiol Endocrinol Metab, 2017, 313(1): E26-E36.
12	DRORI A, GAMMAL A, AZAR S, et al. CB₁R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance[J]. eLife, 2020, 9: e60771.
13	OSEI-HYIAMAN D, DEPETRILLO M, PACHER P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity[J]. J Clin Invest, 2005, 115(5): 1298-1305.
14	CHANDA D, KIM Y H, KIM D K, et al. Activation of cannabinoid receptor type 1 (Cb1r) disrupts hepatic insulin receptor signaling via cyclic AMP-response element-binding protein H (Crebh)-mediated induction of Lipin1 gene[J]. J Biol Chem, 2012, 287(45): 38041-38049.
15	ALSWAT K A. The role of endocannabinoids system in fatty liver disease and therapeutic potentials[J]. Saudi J Gastroenterol, 2013, 19(4): 144-151.
16	KIM Y, GAUTAM S, ASEER K R, et al. Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling[J]. Cell Death Dis, 2020, 11(12): 1044.
17	DUKIĆ M, RADONJIĆ T, JOVANOVIĆ I, et al. Alcohol, inflammation, and microbiota in alcoholic liver disease[J]. Int J Mol Sci, 2023, 24(4): 3735.
18	CHOI W M, KIM H H, KIM M H, et al. Glutamate signaling in hepatic stellate cells drives alcoholic steatosis[J]. Cell Metab, 2019, 30(5): 877-889.e7.
19	REZQ S, HASSAN R, MAHMOUD M F. Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways[J]. Int Immunopharmacol, 2021, 100: 108140.
20	CORRADO A, BATTLE M, WISE S K, et al. Endocannabinoid receptor CB2R is significantly expressed in aspirin-exacerbated respiratory disease: a pilot study[J]. Int Forum Allergy Rhinol, 2018, 8(10): 1184-1189.
21	CAI S L, FAN X G, WU J, et al. CB2R agonist GW405833 alleviates acute liver failure in mice via inhibiting HIF-1α-mediated reprogramming of glycometabolism and macrophage proliferation[J]. Acta Pharmacol Sin, 2023, 44(7): 1391-1403.
22	HUANG Z B, ZHENG Y X, LI N, et al. Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice[J]. Acta Pharmacol Sin, 2019, 40(11): 1404-1411.
23	TEIXEIRA-CLERC F, BELOT M P, MANIN S, et al. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration[J]. Hepatology, 2010, 52(3): 1046-1059.
24	CAO Z X, MULVIHILL M M, MUKHOPADHYAY P, et al. Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice[J]. Gastroenterology, 2013, 144(4): 808-817.e15.
25	FAROOQUI M T, KHAN M A, CHOLANKERIL G, et al. Marijuana is not associated with progression of hepatic fibrosis in liver disease: a systematic review and meta-analysis[J]. Eur J Gastroenterol Hepatol, 2019, 31(2): 149-156.
26	MBOUMBA BOUASSA R S, SEBASTIANI G, DI MARZO V, et al. Cannabinoids and chronic liver diseases[J]. Int J Mol Sci, 2022, 23(16): 9423.
27	KISSELEVA T, BRENNER D A. The crosstalk between hepatocytes, hepatic macrophages, and hepatic stellate cells facilitates alcoholic liver disease[J]. Cell Metab, 2019, 30(5): 850-852.
28	JIANG X Y, GU Y Y, HUANG Y L, et al. CBD alleviates liver injuries in alcoholics with high-fat high-cholesterol diet through regulating NLRP3 inflammasome-pyroptosis pathway[J]. Front Pharmacol, 2021, 12: 724747.
29	WATT M J, MIOTTO P M, DE NARDO W, et al. The liver as an endocrine organ-linking NAFLD and insulin resistance[J]. Endocr Rev, 2019, 40(5): 1367-1393.
30	CINAR R, GODLEWSKI G, LIU J, et al. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides[J]. Hepatology, 2014, 59(1): 143-153.
31	WANG S M, ZHU Q Z, LIANG G S, et al. Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD[J]. J Clin Invest, 2021, 131(22): e152242.
32	LOTERSZTAJN S, MALLAT A. Does CB-1 in hepatic stellate cells contribute to liver fibrosis?[J]. J Clin Invest, 2022, 132(1): e155413.
33	DEVEAUX V, CADOUDAL T, ICHIGOTANI Y, et al. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis[J]. PLoS One, 2009, 4(6): e5844.
34	PALOMARES B, RUIZ-PINO F, GARRIDO-RODRIGUEZ M, et al. Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity[J]. Biochem Pharmacol, 2020, 171: 113693.
35	MARTIN G G, LANDROCK D, DANGOTT L J, et al. Human liver fatty acid binding protein-1 T94A variant, nonalcohol fatty liver disease, and hepatic endocannabinoid system[J]. Lipids, 2018, 53(1): 27-40.
36	BASU P P, ALOYSIUS M M, SHAH N J, et al. Review article: the endocannabinoid system in liver disease, a potential therapeutic target[J]. Aliment Pharmacol Ther, 2014, 39(8): 790-801.
37	HEGDE V L, HEGDE S, CRAVATT B F, et al. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells[J]. Mol Pharmacol, 2008, 74(1): 20-33.
38	TAKHEAW N, JINDAPHUN K, PATA S, et al. Cannabinoid receptor 1 agonist ACEA and cannabinoid receptor 2 agonist GW833972A attenuates cell-mediated immunity by different biological mechanisms[J]. Cells, 2023, 12(6): 848.
39	PATSENKER E, SACHSE P, CHICCA A, et al. Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation[J]. Int J Mol Sci, 2015, 16(4): 7057-7076.
40	SUN L J, YU J W, WAN L, et al. Endocannabinoid system activation contributes to glucose metabolism disorders of hepatocytes and promotes hepatitis C virus replication[J]. Int J Infect Dis, 2014, 23: 75-81.
41	BEYOĞLU D, SCHWALM S, SEMMO N, et al. Hepatitis C virus infection upregulates plasma phosphosphingolipids and endocannabinoids and downregulates lysophosphoinositols[J]. Int J Mol Sci, 2023, 24(2): 1407.
42	HU P, WILHELM J, GERRESHEIM G K, et al. Lnc-ITM2C-1 and GPR55 are proviral host factors for hepatitis C virus[J]. Viruses, 2019, 11(6): 549.
43	MONTALBANO R, HONRATH B, WISSNIOWSKI T T, et al. Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells[J]. Oncotarget, 2016, 7(15): 20312-20323.
44	DADGAR T, EBRAHIMI N, GHOLIPOUR A R, et al. Targeting the metabolism of cancer stem cells by energy disruptor molecules[J]. Crit Rev Oncol Hematol, 2022, 169: 103545.
45	MUKHOPADHYAY B, SCHUEBEL K, MUKHOPADHYAY P, et al. Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms[J]. Hepatology, 2015, 61(5): 1615-1626.
46	SUK K T, MEDERACKE I, GWAK G Y, et al. Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis[J]. Gut, 2016, 65(10): 1721-1732.
47	VARA D, SALAZAR M, OLEA-HERRERO N, et al. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy[J]. Cell Death Differ, 2011, 18(7): 1099-1111.
48	EBRAHIMI N, FAR N P, FAKHR S S, et al. The endocannabinoid system, a new gatekeeper in the pharmacology of human hepatocellular carcinoma[J]. Environ Res, 2023, 228: 115914.

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[9]	ZHENG Ying, XIAO Xin-yi, YANG Zhuo-yi, ZHOU Mei-qi, CHEN Hui, YUAN Yun-sheng. Protective effect of recombinant human IL-1Ra on hepatocytes in vitro [J]. , 2019, 39(10): 1115-.
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[11]	LIU Bin, ZHANG Li, REN Hong, HU Peng. Relationship between proportions of peripheral natural kill cells and dendritic cells and liver injury in patients with chronic hepatitis B virus infection#br# [J]. , 2017, 37(8): 1094-.
[12]	YE Fei, LU Xiao-xiao, LIU Zi-yu, et al. Therapeutic effect of Jinlida granules on the liver injury of mice with type 1 diabetes mellitus and possible mechanisms [J]. , 2016, 36(2): 206-.
[13]	ZHANG Qi. Protective effects of luteolin on immune-mediated liver injury in mice [J]. , 2014, 34(3): 329-.
[14]	DAI Hui-juan, ZHAI Xiu-yu, LI Da-wei, et al. Effects of adenosine A2A receptor agonist CGS21680 on concanavalin-induced acute hepatic injury of mice [J]. , 2014, 34(10): 1459-.
[15]	ZHAO Ze-fei, ZHAO Yong-ju, GU Ming-jun, et al. Effect of Ganoderma lucidum polysaccharides on hyperthyroidism and liver injury in Graves´\|disease mice model [J]. , 2013, 33(5): 607-.