Journal of Uludağ University Medical Faculty

1300-414X 2645-9027

Bursa Uludağ University

10.32708/uutfd.1539347

Gastroenterology and Hepatology

Gastroenteroloji ve Hepatoloji

Hepatic Expression of Endocannabinoid Receptors (CB1 and CB2) in Patients with Non-Alcoholic Steatohepatitis and Its Relationship with Metabolic Syndrome

Non-Alkolik Steatohepatitli Hastalarda Hepatik Endokannabinoid Reseptör CB1 ve CB2 ekspresyonu ve Metabolik Sendromla İlişkisi

https://orcid.org/0000-0002-6174-0817

Eroğlu Haktanır

Ayça

Kocaeli University Faculty of Medicine, Department of Gastroenterology, Kocaeli, Türkiye.

https://orcid.org/0000-0002-7188-6115

Öz Atalay

Fatma

Bursa Uludağ University Faculty of Medicine, Department of Pathology, Bursa, Türkiye.

https://orcid.org/0000-0003-1075-7499

Ayyıldız

Talat

Ondokuz Mayıs University Faculty of Medicine, Department of Gastroenterology, Samsun, Türkiye.

https://orcid.org/0000-0002-5039-164X

Balaban

Saduman

Bursa Uludağ University Faculty of Medicine, Department of Pathology, Bursa, Türkiye.

https://orcid.org/0000-0001-8944-2793

Dolar

Mahmut Enver

Bursa Uludağ University Faculty of Medicine, Department of Gastroenterology, Bursa, Türkiye.

01 12 2025

50 3 381 389 08 27 2024 10 23 2024

1975

Journal of Uludağ University Medical Faculty

The pathogenetic pathways in the progression from steatosis to NASH have not yet been fully elucidated. Recent studies reported that the endocannabinoid system has a role in a variety of steps during chronic liver disease. Endocannabinoids are endogenous lipid mediators with a mechanism of action through activating cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Stimulation of the CB1 receptors increases hepatic fatty acid synthesis. Expression of CB2 receptors in fatty liver may be indicative of their association with metabolic syndrome. The fact that the endocannabinoid system activates various metabolic functions in peripheral tissues suggests that this system may play a role in the treatment of various diseases. In this study, we examined whether metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are associated with expression of cannabinoid receptors. Fifty-four individuals with nonalcoholic steatohepatitis (NASH) and 17 with steatosis based on pathology reports of liver biopsies were included in the patient group. Forty individuals whose liver tissue samples revealed hemangioma, focal nodules and/or simple cyst, and liver areas and liver tissues that were normal in pathology reports were selected as the control group. The association between cannabinoid receptor-1 (CB-1R) and -2 (CB-2R) expression, determined immunohistochemically, and metabolic syndrome criteria and NAS score were determined. A comparison of control (n = 40), steatosis (n = 17)and NASH groups (n = 54) revealed a significant difference in CB-2R expression between patients with steatosis and patients withNASH. The expression of CB-2 receptor in the steatosis group was statistically significantly higher than in the NASH group (p = 0.017). But showed no significant difference in CB-2R expression between NAFLD and control groups (p = 0.924). In our study, it was determined thatCannabinoid receptors-2 (CB-2Rs) were expressed in the liver cells of all patients and the control groups. In addition, the expression of thesereceptors was found to be associated with various parameters such as arterial hypertension, obesity, hyperlipidemia and lobularinflammation.

Steatozdan NASH’a progresyona sebep olan patojenik metabolik yolaklar tam olarak açıklığa kavuşmamıştır. Son dönemdeki çalışmalarda endokannabinoid sistemin kronik karaciğer hastalığı sürecinde pek çok basamakta rol oynayabileceği belirtilmiştir. Endokannabinoidler canlılarda, Cannabinoid reseptör 1 (CB1) ve Cannabinoid reseptör 2’yi (CB2) aktive ederek etkinliklerini gösteren endojen lipid mediyatörlerdir. Endokannabinoid sistemin kronik karaciğer hastalığı sürecinde pek çok basamakta rol oynayabileceği belirtilmiştir. CB1 reseptörlerinin uyarılması hepatik yağ asidi sentezini arttırdığı ve yağlı karaciğerde CB2 reseptörlerinin eksprese olduğunun gösterilmesi bu reseptörlerin metabolik sendromla ilişkili olabileceğinin göstergesi olabilir. Endokannabinoid sistemin periferik dokularda çeşitli metabolik fonksiyonları aktive etmesi, bu sistemin çeşitli hastalıkların tedavisinde rol oynayabileceğini düşündürmektedir. Bizim çalışmamızda metabolik sendrom ve Nonalkolik yağlı karaciğer hastalığıyla cannabinoid reseptörlerinin ekspresyonu arasında ilişki olup olmadığı belirlenmiştir. Karaciğer biyopsilerinin patolojisi raporu NASH olan 54; Steatoz olan 17 kişi hasta grubuna dahil edildi. Karaciğer doku örneklerinde hemanjiom, fokal nodüler hiperplazi, basit kist saptananların patoloji preperatlarındaki normal karaciğer alanları ve normal karaciğer dokusu olarak raporlanan 40 kişi kontrol grubu olarak seçildi. İmmunhistokiyasal olarak CB1 ve CB2 Reseptörleri ile boyanma olup olmadığı, boyanmanın metabolik sendrom kriterleri ve NAS skoru ile olan ilişkisi belirlendi. Kontrol (n=40), Steatoz (n=17) ve NASH grubu (n=54) CB2-R ekspresyonu açısından karşılaştırıldıklarında, Steatozlu hastalar ve NASH’li hastaların CB2-R ekspresyonu aralarında anlamlı farklılık saptandı. Steatoz grubunda CB-2 reseptörünün ekspresyonu, NASH grubuna göre istatistiksel olarak anlamlı şekilde daha fazlaydı (p= 0.017). Fakat NAYKH ve kontrol grubundaki hastaların CB2-R ekspresyonu yüzdeleri karşılaştırıldığında iki grup arasında CB2-R ekspresyonu arasında anlamlı farklılık yoktu (p= 0.924). Çalışmamızda Kannabinoid reseptörleri-2’nin (CB-2R'ler), tüm hastaların ve kontrol grubunun karaciğer hücrelerinde eksprese edildiği belirlenmiştir.Ayrıca bu reseptörlerin ekspresyonu, arteriyel hipertansiyon, obezite, hiperlipidemi ve lobüler inflamasyon gibi çeşitli parametrelerle de ilişkili saptanmıştır.

NAFLD CB-2 receptors metabolic syndrome CB-1 receptors

NASH CB1 reseptörler CB2 reseptörler Metabolik sendrom

Uludağ Üniversitesi Bilimsel Araştırma projeleri birimi tarafınca desteklenmiştir.

UAP(T)-2011/4

1.Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K,Rinella M, et al. The diagnosis and management ofnonalcoholic fatty liver disease: Practice guidance from theAmerican Association for the Study of Liver Diseases.Hepatology. 2018; 67:328-357.

2.Kunos G, Osei-Hyiaman D. Endocannabinoids and liverdisease. IV. Endocannabinoid involvement in obesity andhepatic steatosis. Am J Physiol Gastrointest Liver Physiol2008; 294: 1101-4.

3.Teixeira-Clerc F, Belot MP, Manin S, Deveaux V, Cadoudal T,Chobert MN, et al. Beneficial paracrine effects of cannabinoidreceptor 2 on liver injury and regeneration. Hepatology2010;52:1046-59.

4.Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S,Bátkai S, et al. Endocannabinoid activation at hepatic CB1receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298-305

5.Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L,Karsak M, et al. Antifibrogenic role of the cannabinoid receptorCB2 in the liver. Gastroenterology 2005;128:742-55.

6.Siegmund SV, Schwabe RF. Endocannabinoids and liverdisease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2008;294:G357-62.

7.Dai E, Zhang L, Ye L, Wan S, Feng L, Qi Q et al. Hepaticexpression of cannabinoid receptors CB1 and CB2 correlatewith fibrogenesis in patients with chronic hepatitis B. Int J Infect Dis 2017;59:124-130.

8.Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoidsignaling and liver therapeutics. J Hepatol 2013;59:891-6.

9.Chanda D, Neumann D, Glatz JFC. The endocannabinoid system: Overview of an emerging multi-faceted therapeutictarget. Prostaglandins Leukot Essent Fatty Acids 2019;140:51-56.

10.Rossi F, Bellini G, Luongo L, Manzo I, Tolone S, Tortora C, etal. Cannabinoid Receptor 2 as Antiobesity Target:Inflammation, Fat Storage, and Browning Modulation. J Clin Endocrinol Metab 2016;101(9):3469-78.

11.Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F,Louvet A, Manin S, et al. Cannabinoid CB2 receptorpotentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One 2009;4:e5844.

12.Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, et al. Hepatic CB1 receptor is required fordevelopment of diet-induced steatosis, dyslipidemia, andinsulin and leptin resistance in mice. J Clin Invest2008;118:3160-9.

13.Bergholm R, Sevastianova K, Santos A, Kotronen A,Urjansson M, Hakkarainen A, et al. CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion toweight loss in humans. Int J Obes 2013;37:699-703.

14.González-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Santa-Cruz Calvo S, et al. Human CB1 ReceptorIsoforms, present in Hepatocytes and β-cells, are Involved inRegulating Metabolism. Sci Rep 2016;6:33302.

15.Amato G, Khan NS, Maitra R. A patent update on cannabinoidreceptor 1 antagonists (2015-2018). Expert Opin Ther Pat2019;29:261-69.

16.Farooqui MT, Khan MA, Cholankeril G, Khan Z, Mohammed Abdul MK, Li AA, et al. Marijuana is not associated withprogression of hepatic fibrosis in liver disease: a systematicreview and meta-analysis. Eur J Gastroenterol Hepatol.2019;31:149-156.

17.Gatta-Cherifi B, Cota D. New insights on the role of theendocannabinoid system in the regulation of energy balance. IntJ Obes 2016;40(2):210-9.

18.Gottardi A, Spahr L, Ravier-Dall'Antonia F, Hadengue A.Cannabinoid receptor 1 and 2 agonists increase lipidaccumulation in hepatocytes. Liver Int 2010;30:1482-9.

19.Auguet T, Berlanga A, Guiu-Jurado E, Terra X, Martinez S,Aguilar C, et al. Endocannabinoid receptors gene expression inmorbidly obese women with nonalcoholic fatty liver disease.Biomed Res Int 2014;2014:502542.

20.Baldassarre M, Giannone FA, Napoli L, Tovoli A, Ricci CS,Tufoni M, et al. The endocannabinoid system in advanced livercirrhosis: pathophysiological implication and futureperspectives. Liver Int 2013;33:1298-308

21.Expert Panel on Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults. Executive Summary of The ThirdReport of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of HighBlood Cholesterol In Adults (Adult Treatment Panel III).JAMA 2001;285:2486-97.

22.Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histologicalscoring system for nonalcoholic fatty liver disease. Hepatology.2005;41:1313-21.

23.Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P,Ravinet-Trillou C, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obeseZucker fa/fa rats. Hepatology. 2007;46:122-9.

24.Silvestri C, Paris D, Martella A, Melck D, Guadagnino I,Cawthorne M, et al. Two non-psychoactive cannabinoidsreduce intracellular lipid levels and inhibit hepatosteatosis. J Hepatol 2015;62:1382-90.

25.Mallat A, Teixeira-Clerc F, Deveaux V, Manin S, LotersztajnS.The endocannabinoid system as a key mediator during liverdiseases: new insights and therapeutic openings. Br J Pharmacol 2011;163:1432-40.

26.DeLeve LD, Wang X, Kanel GC, Atkinson RD, McCuskey RS.Prevention of hepatic fibrosis in a murine model of metabolicsyndrome with nonalcoholic steatohepatitis. Am J Pathol. 2008;173:993-1001.

27.Rajesh M, Pan H, Mukhopadhyay P, Bátkai S, Osei-Hyiaman D, Haskó G, et al. Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury byattenuating oxidative stress, inflammatory response, andapoptosis. J Leukoc Biol 2007;82:1382-9.

28.Bergholm R, Sevastianova K, Santos A, Kotronen A, Urjansson M, Hakkarainen A, et al. CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans. Int J Obes 2013;37:699-703.

29.Schneeberger M, Everard A, Gómez-Valadés AG, MatamorosS, Ramírez S, Delzenne NM, et al. Akkermansia muciniphilainversely correlates with the onset of inflammation, alteredadipose tissue metabolism and metabolic disorders duringobesity in mice. Sci Rep 2015;5:16643.

30.Després JP, Golay A, Sjöström L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic riskfactors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121-34.

31.Dhopeshwarkar A, Mackie K. CB2 Cannabinoid receptors as atherapeutic target-what does the future hold? Mol Pharmacol.2014;86:430-7.

32.Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54:1217-26.

33.Mahmoud HM, Osman M, Elshabrawy O, Abdallah HMI,Khairallah A. AM-1241 CB2 Receptor Agonist AttenuatesInflammation, Apoptosis and Stimulate Progenitor Cells in BileDuct Ligated Rats. Open Access Maced J Med Sci 2019;7:925-936.