Endocannabinoids, CB1 Receptors, and Liver Disease: Hitting More Than One Bird With the Same Stone

Abstract

See “Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C” by Hézode C, Zafrani ES, Roudot-Thoraval F, et al, on page 432. See “Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C” by Hézode C, Zafrani ES, Roudot-Thoraval F, et al, on page 432. Interest in endocannabinoids and their functions has been growing exponentially in the last decade or so. This reflects not only the unique nature of these recently discovered lipid ligands—endogenous counterparts of the psychoactive component of marijuana; generated “on demand” in the cell membrane from phospholipid precursors, acting as retrograde transmitters in the brain or as autocrine or paracrine mediators in the periphery, and targeting G-protein–coupled receptors CB1 and CB2—but also by the rapidly widening range of biological systems they are found to modulate.1Pacher P. Bátkai S. Kunos G. The endocannabinoid system as an emerging target for pharmacotherapy.Pharmacol Rev. 2006; 58: 389-462Crossref PubMed Scopus (1566) Google Scholar The liver has been an emerging target, where endocannabinoids have been implicated both in the hemodynamic consequences of cirrhosis2Bátkai S. Járai Z. Wagner J.A. et al.Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.Nat Med. 2001; 7: 827-832Crossref PubMed Scopus (317) Google Scholar, 3Bátkai S. Mukhopadhyay P. Harvey-White J. et al.Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats.Am J Physiol Heart Circ Physiol. 2007; 293: H1689-H1695Crossref PubMed Scopus (105) Google Scholar, 4Gaskari S.A. Liu H. Moezi L. et al.Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats.Br J Pharmacol. 2005; 146: 315-323Crossref PubMed Scopus (106) Google Scholar, 5Ros J. Clària J. To-Figueras J. et al.Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.Gastroenterology. 2002; 122: 85-93Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar and in the fibrotic process itself,6Julien B. Grenard P. Teixeira-Clerc F. et al.Antifibrogenic role of the cannabinoid receptor CB2 in the liver.Gastroenterology. 2005; 128: 742-755Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 7Teixeira-Clerc F. Julien B. Grenard P. et al.CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.Nat Med. 2006; 12: 672-676Crossref Scopus (444) Google Scholar as well as in both diet-8Gary-Bobo M. Elachouri G. et al.Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.Hepatology. 2007; 46: 122-129Crossref PubMed Scopus (278) Google Scholar, 9Osei-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 Clin Invest. 2005; 115: 1298-1305Crossref PubMed Scopus (933) Google Scholar and ethanol-induced fatty liver.10Jeong W.I. Osei-Hyiaman D. Park O. et al.Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.Cell Metab. 2008; 7 (in press)Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar These studies used various rodent models, and thus the question of relevance to human pathology is of paramount importance. Although marijuana is the most widely used recreational drug in Western societies, epidemiologic information on the potential hepatic effects of long-term marijuana use has been until recently absent. This may not be surprising in view of the almost exclusive attention to the psychoactive, addictive properties of marijuana in today’s society. This gap was first addressed by a study from Professor Ariane Mallat’s group, which documented a significant positive correlation between the history of long-term, heavy marijuana use and the severity of progression of liver fibrosis.11Hézode C. Roudot-Thoraval F. Nguyen S. et al.Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C.Hepatology. 2005; 42: 63-71Crossref PubMed Scopus (248) Google Scholar These findings appeared counterintuitive in view of earlier observations in rodents from the neighboring laboratory of Professor Sophie Lotersztajn that documented the antifibrogenic action of CB2 receptor activation in the liver.6Julien B. Grenard P. Teixeira-Clerc F. et al.Antifibrogenic role of the cannabinoid receptor CB2 in the liver.Gastroenterology. 2005; 128: 742-755Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar This paradox was resolved by their subsequent demonstration of the profibrogenic effect of CB1 receptor activation,7Teixeira-Clerc F. Julien B. Grenard P. et al.CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.Nat Med. 2006; 12: 672-676Crossref Scopus (444) Google Scholar Δ9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, being an agonist at both CB1 and CB2 receptors. In this issue of Gastroenterology, Hézode et al12Hézode C. Zafrani E.S. Roudot–Thoraval F. et al.Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C.Gastroenterology. 2008; 134: 432-439Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar fill another important gap by providing the first epidemiologic evidence that daily marijuana use for at least 6 months by patients with hepatitis C virus (HCV) infection is an independent predictor of the severity of steatosis. Given the dominance of CB1 receptors in mediating the effects of THC in the liver,11Hézode C. Roudot-Thoraval F. Nguyen S. et al.Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C.Hepatology. 2005; 42: 63-71Crossref PubMed Scopus (248) Google Scholar this finding provides the first evidence that the steatogenic action of the hepatic endocannabinoid/CB1 receptor system, demonstrated earlier in rodents,8Gary-Bobo M. Elachouri G. et al.Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.Hepatology. 2007; 46: 122-129Crossref PubMed Scopus (278) Google Scholar, 9Osei-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 Clin Invest. 2005; 115: 1298-1305Crossref PubMed Scopus (933) Google Scholar is also operative in humans. Importantly, using statistical methods, they demonstrate that the predictive value of daily cannabis smoking is independent of other important predictors of steatosis severity in this study group, such as heavy alcohol or tobacco use, maintenance treatment with methadone or buprenorphine, or HCV genotype 3. It is noteworthy that body mass index tended to be lower among marijuana users than nonusers, and the proportion of obese/overweight individuals was significantly lower among occasional (7.7%) or daily cannabis users (18.4%) than among nonusers (31.5%). This is interesting because the endocannabinoid/CB1 receptor system has been implicated not only in hepatic steatosis but also in diet-induced obesity, CB1 receptor-null mice being resistant to both,9Osei-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 Clin Invest. 2005; 115: 1298-1305Crossref PubMed Scopus (933) Google Scholar, 13Ravinet Trillou C. Delgorge C. Menet C. et al.CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity.Int J Obes Relat Metab Disord. 2004; 28: 640-648Crossref PubMed Scopus (512) Google Scholar and the CB1 receptor antagonist rimonabant has proven effective in reducing weight in obese/overweight individuals.14Després J.P. Golay A. Sjöström L. Rimonabant in Obesity-Lipids Study GroupEffects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.N Engl J Med. 2005; 353: 2121-2134Crossref PubMed Scopus (1291) Google Scholar, 15Pi-Sunyer F.X. Aronne L.J. Heshmati H.M. et al.RIO-North America Study GroupEffect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial.JAMA. 2006; 295: 761-775Crossref PubMed Scopus (1155) Google Scholar, 16Van Gaal L.F. Rissanen A.M. Scheen A.J. et al.RIO-Europe Study GroupEffects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.Lancet. 2005; 365: 1389-1397Abstract Full Text Full Text PDF PubMed Scopus (1398) Google Scholar Unpublished findings from our laboratory indicate that mice with hepatocyte-specific deletion of CB1 receptors are resistant to hepatic steatosis but do become obese on a high-fat diet, suggesting that steatosis, but not the increase in adipose tissue mass, is mediated by hepatic CB1 receptors. The findings by Hézode et al12Hézode C. Zafrani E.S. Roudot–Thoraval F. et al.Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C.Gastroenterology. 2008; 134: 432-439Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar could then suggest that HCV infection sensitizes the hepatic endocannabinoid/CB1 receptor system without a similar effect in extrahepatic tissues, which may account for the steatotic effect of daily marijuana use without an increase in adiposity. The presence of hyperglycemia and/or diabetes was also found to be a strong predictor of hepatic steatosis, but their relatively low incidence in this cohort precluded analyzing the role of daily cannabis use in their development. Future studies involving a larger study population should explore the relationship between long-term daily marijuana use and hyperglycemia/diabetes, given the emerging evidence for the involvement of the endocannabinoid/CB1 receptor system in insulin resistance both in experimental animals17Bermúdez-Siva F.J. Serrano A. Diaz-Molina F.J. et al.Activation of cannabinoid CB1 receptors induces glucose intolerance in rats.Eur J Pharmacol. 2006; 531: 282-284Crossref PubMed Scopus (100) Google Scholar, 18Liu Y.L. Connoley I.P. Wilson C.A. et al.Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice.Int J Obes (Lond). 2005; 29: 183-187Crossref PubMed Scopus (297) Google Scholar, 19Poirier B. Bidouard J.P. Cadrouvele C. et al.The anti-obesity effect of rimonabant is associated with an improved serum lipid profile.Diabetes Obes Metab. 2005; 7: 65-72Crossref PubMed Scopus (193) Google Scholar, 20Ravinet Trillou C. Arnone M. Delgorge C. et al.Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice.Am J Physiol Regul Integr Comp Physiol. 2003; 284: R345-R353Crossref PubMed Scopus (558) Google Scholar and in humans.21Scheen A.J. Finer N. Hollander P. et al.RIO-Diabetes Study GroupEfficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.Lancet. 2006; 368: 1660-1672Abstract Full Text Full Text PDF PubMed Scopus (706) Google Scholar In view of the involvement of endocannabinoids in steatosis of multiple etiologies, it would be very interesting to examine from both mechanistic and therapeutic perspectives whether the genotype-specific induction of steatosis by HCV genotype 3 may involve activation of the hepatic endocannabinoid system. Linking chronic cannabis use to both liver fibrosis11Hézode C. Roudot-Thoraval F. Nguyen S. et al.Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C.Hepatology. 2005; 42: 63-71Crossref PubMed Scopus (248) Google Scholar and steatosis12Hézode C. Zafrani E.S. Roudot–Thoraval F. et al.Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C.Gastroenterology. 2008; 134: 432-439Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar could also suggest the interrelatedness of these 2 processes. The early development of steatosis in response to various fibrogenic stimuli has been documented in the case of carbon tetrachloride,22Cunnane S.C. Hepatic triacylglycerol accumulation induced by ethanol and carbon tetrachloride: interactions with essential fatty acids and prostaglandins.Alc Clin Exp Res. 1987; 11: 25-30Crossref PubMed Scopus (29) Google Scholar alcohol,10Jeong W.I. Osei-Hyiaman D. Park O. et al.Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.Cell Metab. 2008; 7 (in press)Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 22Cunnane S.C. Hepatic triacylglycerol accumulation induced by ethanol and carbon tetrachloride: interactions with essential fatty acids and prostaglandins.Alc Clin Exp Res. 1987; 11: 25-30Crossref PubMed Scopus (29) Google Scholar or HCV infection.23Castera L. Chouteau P. Hézode C. et al.Hepatitis C virus-induced hepatocellular steatosis.Am J Gastroenterol. 2005; 100: 711-715Crossref PubMed Scopus (76) Google Scholar In turn, hepatic steatosis is a well-established forerunner and predisposing factor to liver fibrosis and cirrhosis. Endocannabinoids target CB1 receptors on hepatic stellate cells to promote fibrogenesis,7Teixeira-Clerc F. Julien B. Grenard P. et al.CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.Nat Med. 2006; 12: 672-676Crossref Scopus (444) Google Scholar whereas their lipogenic action is mediated by CB1 receptors on hepatocytes.9Osei-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 Clin Invest. 2005; 115: 1298-1305Crossref PubMed Scopus (933) Google Scholar Using a mouse model of ethanol-induced fatty liver, we recently found that ethanol selectively up-regulates the endocannabinoid 2-arachidonoyl glycerol (2-AG) in hepatic stellate cells, which induces a CB1 receptor-mediated induction of de novo lipogenesis in adjacent hepatocytes, as documented using a coculture paradigm.10Jeong W.I. Osei-Hyiaman D. Park O. et al.Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.Cell Metab. 2008; 7 (in press)Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar This could suggest that in addition to their well established role in fibrogenesis, hepatic stellate cells may also be involved in the initiation of hepatic lipogenesis and steatosis. In addition, Kupffer cells have been shown to play an essential role in both hepatic fibrosis and steatosis.24Adachi Y. Bradford B. Gao W. et al.Inactivation of Kupffer cells prevents early alcohol-induced liver injury.Hepatology. 1994; 20: 453-460Crossref PubMed Scopus (463) Google Scholar, 25Duffield J.S. Forbes S.J. Constandinou C.M. et al.Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J Clin Invest. 2005; 115: 56-65Crossref PubMed Scopus (1239) Google Scholar Furthermore, macrophages (and probably Kupffer cells as well) produce anandamide in response to lipopolysaccharide stimulation.26Liu J. Batkai S. Pacher P. et al.Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kappaB independently of platelet-activating factor.J Biol Chem. 2003; 278: 45034-45039Crossref PubMed Scopus (198) Google Scholar Therefore, one mechanism by which they can contribute to hepatic lipogenesis and fibrogenesis may be via the production of endocannabinoids that subsequently target CB1 receptors on stellate cells and hepatocytes. A hypothetical scheme depicting the fibrogenic and lipogenic actions of endocannabinoids is shown in Figure 1. Whereas the detailed characterization of increasingly complex paracrine mechanisms in the liver obviously requires further studies, the involvement of hepatic endocannabinoids and CB1 receptors in both fibrogenesis and steatosis has practical implications of immediate relevance. Studies in rodent models of hepatic fibrogenesis and steatosis have already documented the effectiveness of treatment with a CB1 receptor antagonist in attenuating fibrosis7Teixeira-Clerc F. Julien B. Grenard P. et al.CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis.Nat Med. 2006; 12: 672-676Crossref Scopus (444) Google Scholar and reversing steatosis.8Gary-Bobo M. Elachouri G. et al.Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.Hepatology. 2007; 46: 122-129Crossref PubMed Scopus (278) Google Scholar Steatosis as well as fibrosis in patients with chronic hepatitis C are major contributors to resistance to interferon treatment,27Gao B. Hong F. Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus.Hepatology. 2004; 39: 880-890Crossref PubMed Scopus (143) Google Scholar and it has been proposed that interventions aiming at ameliorating liver steatosis before antiviral therapy may improve treatment efficacy in HCV patients.28Westin J. Lagging M. Dhillon A.P. et al.DITTO-HCV Study GroupImpact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection.J Viral Hepatol. 2007; 14: 29-35Crossref PubMed Scopus (68) Google Scholar Therefore, based on the very interesting findings of Hézode et al,12Hézode C. Zafrani E.S. Roudot–Thoraval F. et al.Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C.Gastroenterology. 2008; 134: 432-439Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar clinical trials testing the effectiveness of a CB1 antagonist in combination with antiviral interferon treatment in patients with chronic HCV complicated by steatosis and fibrosis may be warranted. An important limitation of the use of CB1 antagonists has been side effects due to blockade of CB1 receptors in the central nervous system, including nausea/vomiting, and an increase in anxiety or depression in susceptible individuals.14Després J.P. Golay A. Sjöström L. Rimonabant in Obesity-Lipids Study GroupEffects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.N Engl J Med. 2005; 353: 2121-2134Crossref PubMed Scopus (1291) Google Scholar, 15Pi-Sunyer F.X. Aronne L.J. Heshmati H.M. et al.RIO-North America Study GroupEffect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial.JAMA. 2006; 295: 761-775Crossref PubMed Scopus (1155) Google Scholar, 16Van Gaal L.F. Rissanen A.M. Scheen A.J. et al.RIO-Europe Study GroupEffects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.Lancet. 2005; 365: 1389-1397Abstract Full Text Full Text PDF PubMed Scopus (1398) Google Scholar Indeed, nausea and depression are known side effects of antiviral interferon therapy,27Gao B. Hong F. Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus.Hepatology. 2004; 39: 880-890Crossref PubMed Scopus (143) Google Scholar and in a recent observational study, occasional to moderate use of cannabis during antiviral treatment of patients with hepatitis C helped the patients to maintain adherence, likely by relieving nausea and attenuating treatment-related mental depression.29Sylvestre D.L. Clements B.J. Malibu Y. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C.Eur J Gastroenterol Hepatol. 2006; 18: 1057-1063Crossref PubMed Scopus (42) Google Scholar To the extent that the steatotic and fibrogenic effects of cannabinoids are mediated by hepatic CB1 receptors, peripherally restricted CB1 antagonists may effectively counteract these effects without causing or aggravating nausea and anxiety/depression. Once developed, such compounds could have considerable therapeutic potential in the management of hepatic steatosis and fibrosis of various etiologies. Daily Cannabis Use: A Novel Risk Factor of Steatosis Severity in Patients With Chronic Hepatitis CGastroenterologyVol. 134Issue 2PreviewBackground & Aims: Steatosis is highly prevalent in patients with chronic hepatitis C (CHC) and has been reported to increase fibrosis and reduce the rate of viral eradication. Two recent studies indicate that endocannabinoids promote experimental steatosis via activation of hepatic CB1 receptors. We therefore investigated the impact of cannabis smoking on steatosis severity during CHC. Methods: A total of 315 consecutive patients with untreated CHC undergoing liver biopsy were included. Detailed histories of recent cannabis, alcohol, and tobacco use were recorded. Full-Text PDF