上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2024 , Vol. 44 >Issue 10: 1299 - 1306

DOI: https://doi.org/10.3969/j.issn.1674-8115.2024.10.012

综述

内源性大麻素系统在肝脏病中作用的研究进展

  • 边姝 ,
  • 于倩 ,
  • 刘亮明
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  • 1.南京医科大学上海松江临床医学院感染科，上海 201600
    2.上海交通大学医学院附属松江医院感染科，上海 201600
边　姝（1998—），女，硕士生；电子信箱：stacybian@163.com。
刘亮明，电子信箱：liuliangming@shsmu.edu.cn。

收稿日期: 2024-04-22

  录用日期: 2024-06-04

  网络出版日期: 2024-10-28

基金资助

国家自然科学基金(81770612);上海市松江区科委科技攻关(2023SJKJGG027)

收起

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

  • Shu BIAN ,
  • Qian YU ,
  • Liangming LIU
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  • 1.Department of Infection, Shanghai Songjiang Clinical Medical College of Nanjing Medical University, Shanghai 201600, China
    2.Department of Infection, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
LIU Liangming, E-mail: liuliangming@shsmu.edu.cn.

Received date: 2024-04-22

  Accepted date: 2024-06-04

  Online published: 2024-10-28

Supported by

National Natural Science Foundation of China(81770612);Science and Technology Research of Songjiang District Science and Technology Commission in Shanghai(2023SJKJGG027)

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摘要

内源性大麻素系统（endocannabinoid system，ECS）是由多种长链不饱和脂肪酸类似物如花生四酰乙醇酰胺（anandamide，AEA）和2-花生四酰甘油（2-arachidonoyl glycerol，2-AG）及其特异性结合G蛋白偶联受体大麻素受体1（cannabinoid receptor 1，CB1R）和大麻素受体2（cannabinoid receptor 2，CB2R）等组成。通过对细胞物质与能量代谢等方面的影响，ECS几乎影响了机体所有细胞的生命进程和生物学活性。在肝脏，生理性ECS仅低水平表达，肝损伤因素的作用，会强烈刺激肝内ECS的表达和分泌。ECS是多种肝脏疾病共同的参与者。已知，ECS参与了肝细胞脂肪变性过程，促进了非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）和酒精性肝病（alcoholic liver disease，ALD）的形成和发展；参与了肝脏疾病的炎症损伤过程，对肝组织的免疫炎症损伤反应有重要影响；参与了肝纤维形成，促进了肝纤维化和肝硬化的发生与发展。文章通过例举脂代谢相关性肝病（NAFLD和ALD）和其他肝脏病，进一步深入阐述了ECS在肝脏疾病发生发展中的作用及机制。

关键词： 内源性大麻素系统; 非酒精性脂肪性肝病; 酒精性肝病; 肝损伤; 肝纤维化

本文引用格式

边姝 , 于倩 , 刘亮明 . 内源性大麻素系统在肝脏病中作用的研究进展[J]. 上海交通大学学报（医学版）, 2024 , 44(10) : 1299 -1306 . DOI: 10.3969/j.issn.1674-8115.2024.10.012

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

参考文献

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, KL?TING 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 DUKI? M, RADONJI? T, JOVANOVI? 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 BEYO?LU 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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