- Email: [email protected]
Endocannabinoids, CB1 Receptors, and Liver Disease: Hitting More Than One Bird With the Same Stone
622
7.
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10. 11.
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HCV RNA level, and liver fibrosis. Gastroenterology 2008;134: 416 – 423. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402– 2410. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50:1844 –1850. Ratziu V, Heurtier A, Bonyhay L, et al. Review article: an unexpected virus-host interaction—the hepatitis C virus-diabetes link. Aliment Pharmacol Ther 2005;22(Suppl 2):56 – 60. Zekry A, McHutchison JG, Diehl AM. Insulin resistance and steatosis in hepatitis C virus infection. Gut 2005;54:903–906. Lai MM. Hepatitis C virus proteins: direct link to hepatic oxidative stress, steatosis, carcinogenesis and more. Gastroenterology 2002;122:568 –571. Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol 2005;42:744 –751. Romero-Gómez M, Castellano-Megias VM, Grande L, et al. Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol 2003;98:1135–1141. Hui JM, Kench J, Farrell GC, et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol 2002;17:873– 881. den Boer M, Voshol PJ, Kuipers F, et al. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. Arterioscler Thromb Vasc Biol 2004;24:644 – 649. Ryysy L, Häkkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49:749 –758.
GASTROENTEROLOGY Vol. 134, No. 2
17. Buettner R, Ottinger I, Scholmerich J, et al. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 2004;286:E828 – 833. 18. Monetti M, Levin MC, Watt MJ, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 2007;6:69 –78. 19. Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology 2004;126:917–919. 20. Moriishi K, Okabayashi T, Nakai K, et al. Proteasome activator PA28g-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol 2003;77:10237–10249. 21. Miyamoto H, Moriishi K, Moriya K, et al. Involvement of the PA28g-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 2007;81:1727–1735. 22. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through upregulation of suppressor of cytokine signaling 3. Am J Pathol 2004;165:1499 –1508. 23. Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology 2003;38:1384 –1392. 24. Harrison SA, Brunt EM, Qazi RA, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2005;3:604 – 609.
Address requests for reprints to: Brent A. Neuschwander–Tetri, MD, Saint Louis University Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, 3635 Vista Avenue, Saint Louis, Missouri 63110. e-mail: [email protected]. © 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2007.12.041
Endocannabinoids, CB1 Receptors, and Liver Disease: Hitting More Than One Bird With the Same Stone
See “Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C” by Hézode C, Zafrani ES, RoudotThoraval F, et al, on page 432.
I
nterest 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.1
The liver has been an emerging target, where endocannabinoids have been implicated both in the hemodynamic consequences of cirrhosis2–5 and in the fibrotic process itself,6,7 as well as in both diet-8,9 and ethanolinduced fatty liver.10 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.11 These findings appeared counterintuitive in view of ear-
February 2008
EDITORIALS
623
Figure 1. Schematic representation of the hepatic fibrogenic and steatogenic actions of endocannabinoids. Fibrogenic stimuli, such as CCl4 or ethanol, selectively induce 2-AG production in stellate cells.10,30 2-AG can then activate CB1 receptors on stellate cells to induce fibrogenesis,7 or on adjacent hepatocytes to induce de novo lipogenesis.10 Lipogenic stimuli, such as a highfat diet, induces anandamide (AEA) production and CB1 expression in hepatocytes, activation of which increases de novo lipogenesis and inhibits fatty acid -oxidation.9 Abbreviations: FAAH, fatty acid amidohydrolase; AMPK, AMP-activated protein kinase; SREBP1c, sterol response element binding protein-1c; ACC1, acetyl CoA carboxylase-1; FAS, fatty acid synthase; SCD1, stearoyl CoA desaturase-1; CPT1, carnitine palmitoyl transferase-1.
lier observations in rodents from the neighboring laboratory of Professor Sophie Lotersztajn that documented the antifibrogenic action of CB2 receptor activation in the liver.6 This paradox was resolved by their subsequent demonstration of the profibrogenic effect of CB1 receptor activation,7 ⌬9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, being an agonist at both CB1 and CB2 receptors. In this issue of GASTROENTEROLOGY, Hézode et al12 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,11 this finding provides the first evidence that the steatogenic action of the hepatic endocannabinoid/CB1 receptor system, demonstrated earlier in rodents,8,9 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,9,13 and the CB1 receptor antagonist rimonabant has proven effective in reducing weight in obese/overweight individuals.14 –16 Unpublished findings from our laboratory indicate that mice with hepatocytespecific 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 al12 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 animals17–20 and in humans.21 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.
624
EDITORIALS
Linking chronic cannabis use to both liver fibrosis11 and steatosis12 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,22 alcohol,10,22 or HCV infection.23 In turn, hepatic steatosis is a wellestablished forerunner and predisposing factor to liver fibrosis and cirrhosis. Endocannabinoids target CB1 receptors on hepatic stellate cells to promote fibrogenesis,7 whereas their lipogenic action is mediated by CB1 receptors on hepatocytes.9 Using a mouse model of ethanolinduced 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.10 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.24,25 Furthermore, macrophages (and probably Kupffer cells as well) produce anandamide in response to lipopolysaccharide stimulation.26 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 fibrosis7 and reversing steatosis.8 Steatosis as well as fibrosis in patients with chronic hepatitis C are major contributors to resistance to interferon treatment,27 and it has been proposed that interventions aiming at ameliorating liver steatosis before antiviral therapy may improve treatment efficacy in HCV patients.28 Therefore, based on the very interesting findings of Hézode et al,12 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.14 –16 Indeed, nausea and depression are known side effects of antiviral interferon therapy,27 and in a recent observational study, occasional to moderate
GASTROENTEROLOGY Vol. 134, No. 2
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.29 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.
GEORGE KUNOS Section on Neuroendocrinology BIN GAO Section on Liver Biology Laboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda, Maryland References 1. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target for pharmacotherapy. Pharmacol Rev 2006;58: 389 – 462. 2. Bátkai S, Járai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827– 832. 3. Bátkai 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 –1695. 4. Gaskari SA, Liu H, Moezi L, et al. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Br J Pharmacol 2005;146:315–323. 5. Ros 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;122:85–93. 6. Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005;128:742–755. 7. Teixeira-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– 676. 8. Gary-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;46:122–129. 9. 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 Clin Invest 2005; 115:1298 –1305. 10. Jeong WI, 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). 11. Hézode 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;42:63–71. 12. Hézode C, Zafrani ES, 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– 439.
February 2008
13. Ravinet Trillou C, Delgorge C, Menet C, et al. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to dietinduced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 2004;28:640 – 648. 14. Després JP, Golay A, Sjöström L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353: 2121–2134. 15. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al; RIO-North America Study Group. Effect 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;295:761–775. 16. Van Gaal LF, Rissanen AM, Scheen AJ, et al; RIO-Europe Study Group. Effects 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 –1397. 17. Bermúdez-Siva FJ, Serrano A, Diaz-Molina FJ, et al. Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol 2006;531:282–284. 18. Liu YL, Connoley IP, Wilson CA, 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;29:183–187. 19. Poirier B, Bidouard JP, Cadrouvele C, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 2005;7:65–72. 20. Ravinet 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– 353. 21. Scheen AJ, Finer N, Hollander P, et al; RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368:1660 –1672.
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22. Cunnane SC. Hepatic triacylglycerol accumulation induced by ethanol and carbon tetrachloride: interactions with essential fatty acids and prostaglandins. Alc Clin Exp Res 1987;11:25–30. 23. Castera L, Chouteau P, Hézode C, et al. Hepatitis C virus-induced hepatocellular steatosis. Am J Gastroenterol 2005;100:711–715. 24. Adachi Y, Bradford B, Gao W, et al. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 1994;20:453–460. 25. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005;115:56 – 65. 26. Liu 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 – 45039. 27. Gao B, Hong F, Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus. Hepatology 2004;39:880–890. 28. Westin J, Lagging M, Dhillon AP, et al. DITTO-HCV Study Group. Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection. J Viral Hepatol 2007;14:29 –35. 29. Sylvestre DL, Clements BJ, Malibu Y. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. Eur J Gastroenterol Hepatol 2006;18:1057–1063. 30. Siegmund SV, Qian T, de Minicis S, et al. The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J 2007;21:2798–2806.
Address request for reprints to: George Kunos, MD, PhD, Section on Neuroendocrinology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892. e-mail: [email protected] © 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2007.12.017
Autoimmune Pancreatitis, Part II: The Relapse
See “Substitution of aspartic acid at position 57 of the DQ1 affects relapse of autoimmune pancreatitis” by Park DH, Kim M-H, Oh HB, et al, on page 440.
A
utoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic disease characterized by a steroid-responsive fibroinflammatory process involving multiple organs, including the pancreas, bile duct, retroperitoneum, and salivary and lacrimal glands. The term IgG4associated systemic disease (ISD) has been used to describe this multisystem disorder1 (Figure 1) because it is characterized by a peculiar elevation in serum levels of the IgG4 subclass of immunoglobulin G and tissue infiltration with abundant IgG4-positive plasma cells. Patients with AIP often have
other organs involved as part of ISD. These include chronic sclerosing sialadenitis (CSS), IgG4-associated retroperitoneal fibrosis (IRPF), IgG4-associated nephritis (ITIN), IgG4associated cholangitis (IAC) (Figure 1). The frequency of other organ involvement varies depending on which organ is the focus of study as the primary manifestation. Whether AIP is necessarily “the center of the universe” of ISD is not clear. Many organs involved in ISD share common histologic features of abundant infiltration with lymphocytes and plasma cells accompanied by an intense and characteristically swirling (storiform) fibrosis. The infiltrate has a unique predilection to involve veins, leading to their obstruction (obliterative phlebitis) while sparing the neighboring artery. In the pancreas, this combination of histologic features has been termed lymphoplasmacytic sclerosing pancreatitis (LPSP), which is diagnostic of AIP,2 but similar features have been described in IgG4-associated cholangitis and
7.
8.
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10. 11.
12.
13.
14.
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HCV RNA level, and liver fibrosis. Gastroenterology 2008;134: 416 – 423. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402– 2410. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50:1844 –1850. Ratziu V, Heurtier A, Bonyhay L, et al. Review article: an unexpected virus-host interaction—the hepatitis C virus-diabetes link. Aliment Pharmacol Ther 2005;22(Suppl 2):56 – 60. Zekry A, McHutchison JG, Diehl AM. Insulin resistance and steatosis in hepatitis C virus infection. Gut 2005;54:903–906. Lai MM. Hepatitis C virus proteins: direct link to hepatic oxidative stress, steatosis, carcinogenesis and more. Gastroenterology 2002;122:568 –571. Abid K, Pazienza V, de Gottardi A, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol 2005;42:744 –751. Romero-Gómez M, Castellano-Megias VM, Grande L, et al. Serum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol 2003;98:1135–1141. Hui JM, Kench J, Farrell GC, et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol 2002;17:873– 881. den Boer M, Voshol PJ, Kuipers F, et al. Hepatic steatosis: a mediator of the metabolic syndrome. Lessons from animal models. Arterioscler Thromb Vasc Biol 2004;24:644 – 649. Ryysy L, Häkkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000; 49:749 –758.
GASTROENTEROLOGY Vol. 134, No. 2
17. Buettner R, Ottinger I, Scholmerich J, et al. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 2004;286:E828 – 833. 18. Monetti M, Levin MC, Watt MJ, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 2007;6:69 –78. 19. Weinman SA, Belalcazar LM. Hepatitis C: a metabolic liver disease. Gastroenterology 2004;126:917–919. 20. Moriishi K, Okabayashi T, Nakai K, et al. Proteasome activator PA28g-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol 2003;77:10237–10249. 21. Miyamoto H, Moriishi K, Moriya K, et al. Involvement of the PA28g-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 2007;81:1727–1735. 22. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through upregulation of suppressor of cytokine signaling 3. Am J Pathol 2004;165:1499 –1508. 23. Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology 2003;38:1384 –1392. 24. Harrison SA, Brunt EM, Qazi RA, et al. Effect of significant histologic steatosis or steatohepatitis on response to antiviral therapy in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2005;3:604 – 609.
Address requests for reprints to: Brent A. Neuschwander–Tetri, MD, Saint Louis University Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, 3635 Vista Avenue, Saint Louis, Missouri 63110. e-mail: [email protected]. © 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2007.12.041
Endocannabinoids, CB1 Receptors, and Liver Disease: Hitting More Than One Bird With the Same Stone
See “Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C” by Hézode C, Zafrani ES, RoudotThoraval F, et al, on page 432.
I
nterest 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.1
The liver has been an emerging target, where endocannabinoids have been implicated both in the hemodynamic consequences of cirrhosis2–5 and in the fibrotic process itself,6,7 as well as in both diet-8,9 and ethanolinduced fatty liver.10 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.11 These findings appeared counterintuitive in view of ear-
February 2008
EDITORIALS
623
Figure 1. Schematic representation of the hepatic fibrogenic and steatogenic actions of endocannabinoids. Fibrogenic stimuli, such as CCl4 or ethanol, selectively induce 2-AG production in stellate cells.10,30 2-AG can then activate CB1 receptors on stellate cells to induce fibrogenesis,7 or on adjacent hepatocytes to induce de novo lipogenesis.10 Lipogenic stimuli, such as a highfat diet, induces anandamide (AEA) production and CB1 expression in hepatocytes, activation of which increases de novo lipogenesis and inhibits fatty acid -oxidation.9 Abbreviations: FAAH, fatty acid amidohydrolase; AMPK, AMP-activated protein kinase; SREBP1c, sterol response element binding protein-1c; ACC1, acetyl CoA carboxylase-1; FAS, fatty acid synthase; SCD1, stearoyl CoA desaturase-1; CPT1, carnitine palmitoyl transferase-1.
lier observations in rodents from the neighboring laboratory of Professor Sophie Lotersztajn that documented the antifibrogenic action of CB2 receptor activation in the liver.6 This paradox was resolved by their subsequent demonstration of the profibrogenic effect of CB1 receptor activation,7 ⌬9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, being an agonist at both CB1 and CB2 receptors. In this issue of GASTROENTEROLOGY, Hézode et al12 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,11 this finding provides the first evidence that the steatogenic action of the hepatic endocannabinoid/CB1 receptor system, demonstrated earlier in rodents,8,9 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,9,13 and the CB1 receptor antagonist rimonabant has proven effective in reducing weight in obese/overweight individuals.14 –16 Unpublished findings from our laboratory indicate that mice with hepatocytespecific 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 al12 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 animals17–20 and in humans.21 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.
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Linking chronic cannabis use to both liver fibrosis11 and steatosis12 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,22 alcohol,10,22 or HCV infection.23 In turn, hepatic steatosis is a wellestablished forerunner and predisposing factor to liver fibrosis and cirrhosis. Endocannabinoids target CB1 receptors on hepatic stellate cells to promote fibrogenesis,7 whereas their lipogenic action is mediated by CB1 receptors on hepatocytes.9 Using a mouse model of ethanolinduced 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.10 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.24,25 Furthermore, macrophages (and probably Kupffer cells as well) produce anandamide in response to lipopolysaccharide stimulation.26 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 fibrosis7 and reversing steatosis.8 Steatosis as well as fibrosis in patients with chronic hepatitis C are major contributors to resistance to interferon treatment,27 and it has been proposed that interventions aiming at ameliorating liver steatosis before antiviral therapy may improve treatment efficacy in HCV patients.28 Therefore, based on the very interesting findings of Hézode et al,12 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.14 –16 Indeed, nausea and depression are known side effects of antiviral interferon therapy,27 and in a recent observational study, occasional to moderate
GASTROENTEROLOGY Vol. 134, No. 2
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.29 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.
GEORGE KUNOS Section on Neuroendocrinology BIN GAO Section on Liver Biology Laboratory of Physiologic Studies National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda, Maryland References 1. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target for pharmacotherapy. Pharmacol Rev 2006;58: 389 – 462. 2. Bátkai S, Járai Z, Wagner JA, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827– 832. 3. Bátkai 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 –1695. 4. Gaskari SA, Liu H, Moezi L, et al. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Br J Pharmacol 2005;146:315–323. 5. Ros 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;122:85–93. 6. Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005;128:742–755. 7. Teixeira-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– 676. 8. Gary-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;46:122–129. 9. 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 Clin Invest 2005; 115:1298 –1305. 10. Jeong WI, 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). 11. Hézode 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;42:63–71. 12. Hézode C, Zafrani ES, 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– 439.
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13. Ravinet Trillou C, Delgorge C, Menet C, et al. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to dietinduced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord 2004;28:640 – 648. 14. Després JP, Golay A, Sjöström L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353: 2121–2134. 15. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al; RIO-North America Study Group. Effect 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;295:761–775. 16. Van Gaal LF, Rissanen AM, Scheen AJ, et al; RIO-Europe Study Group. Effects 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 –1397. 17. Bermúdez-Siva FJ, Serrano A, Diaz-Molina FJ, et al. Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol 2006;531:282–284. 18. Liu YL, Connoley IP, Wilson CA, 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;29:183–187. 19. Poirier B, Bidouard JP, Cadrouvele C, et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes Metab 2005;7:65–72. 20. Ravinet 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– 353. 21. Scheen AJ, Finer N, Hollander P, et al; RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006;368:1660 –1672.
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22. Cunnane SC. Hepatic triacylglycerol accumulation induced by ethanol and carbon tetrachloride: interactions with essential fatty acids and prostaglandins. Alc Clin Exp Res 1987;11:25–30. 23. Castera L, Chouteau P, Hézode C, et al. Hepatitis C virus-induced hepatocellular steatosis. Am J Gastroenterol 2005;100:711–715. 24. Adachi Y, Bradford B, Gao W, et al. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 1994;20:453–460. 25. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005;115:56 – 65. 26. Liu 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 – 45039. 27. Gao B, Hong F, Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus. Hepatology 2004;39:880–890. 28. Westin J, Lagging M, Dhillon AP, et al. DITTO-HCV Study Group. Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection. J Viral Hepatol 2007;14:29 –35. 29. Sylvestre DL, Clements BJ, Malibu Y. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. Eur J Gastroenterol Hepatol 2006;18:1057–1063. 30. Siegmund SV, Qian T, de Minicis S, et al. The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J 2007;21:2798–2806.
Address request for reprints to: George Kunos, MD, PhD, Section on Neuroendocrinology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892. e-mail: [email protected] © 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2007.12.017
Autoimmune Pancreatitis, Part II: The Relapse
See “Substitution of aspartic acid at position 57 of the DQ1 affects relapse of autoimmune pancreatitis” by Park DH, Kim M-H, Oh HB, et al, on page 440.
A
utoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic disease characterized by a steroid-responsive fibroinflammatory process involving multiple organs, including the pancreas, bile duct, retroperitoneum, and salivary and lacrimal glands. The term IgG4associated systemic disease (ISD) has been used to describe this multisystem disorder1 (Figure 1) because it is characterized by a peculiar elevation in serum levels of the IgG4 subclass of immunoglobulin G and tissue infiltration with abundant IgG4-positive plasma cells. Patients with AIP often have
other organs involved as part of ISD. These include chronic sclerosing sialadenitis (CSS), IgG4-associated retroperitoneal fibrosis (IRPF), IgG4-associated nephritis (ITIN), IgG4associated cholangitis (IAC) (Figure 1). The frequency of other organ involvement varies depending on which organ is the focus of study as the primary manifestation. Whether AIP is necessarily “the center of the universe” of ISD is not clear. Many organs involved in ISD share common histologic features of abundant infiltration with lymphocytes and plasma cells accompanied by an intense and characteristically swirling (storiform) fibrosis. The infiltrate has a unique predilection to involve veins, leading to their obstruction (obliterative phlebitis) while sparing the neighboring artery. In the pancreas, this combination of histologic features has been termed lymphoplasmacytic sclerosing pancreatitis (LPSP), which is diagnostic of AIP,2 but similar features have been described in IgG4-associated cholangitis and