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system liver Cannabinoid injury &

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06.06.2018

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  • system liver Cannabinoid injury &
  • The endocannabinoid system and liver diseases.
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  • Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a. The EC system is highly up-regulated during chronic liver diseases and, to date, it has been implicated in the pathogenesis of non-alcoholic fatty liver disease. Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow-Derived Monocytes/Macrophages in a.

    system liver Cannabinoid injury &

    The underlying mechanisms are not completely understood, although there is evidence for the pathogenic role of ammonia, alterations in various central neurotransmitter systems as well as altered cerebrovascular function. Mice with thioacetamide-induced fulminant liver failure have elevated brain 2-AG content. Treatment of such mice with 2-AG or the CB 2 agonist HU improved the neurological score and cognitive function, and these effects were blocked by a CB 2 antagonist.

    The beneficial effects of CB 2 agonists could be mimicked by treatment with the CB 1 antagonist rimonabant CBD was found to improve cognitive and motor function as well as the neuroinflammation found in hepatic encephalopathy The cerebral inflammatory response of mice to BDL was reduced by CBD treatment, and the effect was attributed to indirect activation of hippocampal A2A adenosine receptors.

    It is possible that combined treatment with a CB 2 agonists and CBD offers additive therapeutic benefits in hepatic encephalopathy. In a murine model of concanavalin A ConA -induced autoimmune hepatitis, THC attenuated the hepatitis, as judged by decreased plasma levels of liver enzymes and inflammatory cytokines and reduced tissue injury In contrast, the results of another study suggest that hepatoprotection may be achieved by blocking CB 1 receptors The ECS is present in the liver and is involved in the control of various hepatic functions with important therapeutic implications.

    Increased CB 1 activity contributes to the hemodynamic abnormalities and promotes fibrosis in liver cirrhosis, whereas CB 1 blockade attenuates and delays these changes. Endocannabinoids acting via hepatic CB 1 receptors have emerged as mediators of both diet-induced and alcoholic fatty liver which, together, account for the majority of cirrhosis in Western societies. Additionally, hepatic CB 1 activation contributes to obesity-related insulin- and leptin-resistance and dyslipidemias. This provides strong rationale for the therapeutic use of CB 1 antagonists in these conditions.

    Although neuropsychiatric side effects limit the therapeutic potential of brain-penetrant CB 1 antagonists, the recent emergence of second generation, peripherally-restricted CB 1 antagonists may mitigate this problem. Additionally, non-psychoactive CB 2 agonists may offer therapeutic benefit in attenuating liver injury and promoting tissue repair in the fibrotic liver.

    National Center for Biotechnology Information , U. Author manuscript; available in PMC Jan 1. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Hepatology. See other articles in PMC that cite the published article. Abstract Endocannabinoids are lipid mediators of the same cannabinoid CB receptors that mediate the effects of marijuana.

    The Endocannabinoid System Marijuana has been used for its psychoactive and medicinal properties for millennia. Open in a separate window. Cellular distribution of hepatic CB1 and CB2 receptors and their involvement in liver diseases Numbers in parentheses refer to original reports as listed in References.

    Endocannabinoids and Altered Hemodynamics in Cirrhosis The potent hypotensive action of THC has long been recognized and it even prompted attempts to exploit it for the treatment of hypertension Endocannabinoids and Liver Fibrosis CB 2 receptors, which are normally undetectable in the liver, are prominently expressed in the cirrhotic human liver, and are also detectable in non-parenchymal liver cells in fibrotic mouse liver 9. Endocannabinoids and the Metabolic Syndrome The CB 1 -mediated appetite promoting effect of endocannabinoids 60 was the primary impetus for the development of brain-penetrant CB 1 receptor antagonists for the treatment of obesity.

    CB1 mechanisms involved in liver fat accumulation The major pathway is CB1 activation of lipoprotein lipase LPL in adipose tissue, resulting in increased fatty-acid FA release and transfer to liver Alcoholic Fatty Liver Chronic alcoholism may lead to steatosis that can further progress into steatohepatitis, liver cirrhosis and hepatocellular carcinoma. Hepatic Encephalopathy, Autoimmune Hepatitis Hepatic encephalopathy is a neuropsychiatric syndrome that may accompany acute liver failure.

    Concluding Remarks The ECS is present in the liver and is involved in the control of various hepatic functions with important therapeutic implications. The endocannabinoid system as an emerging target of pharmacotherapy. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice.

    CB1 cannabinoid receptor antagonism: HGF-, EGF-, and dexamethasone-induced gene expression patterns during formation of tissue in hepatic organoid cultures. Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma.

    Hepatic expression of endocannabinoid receptors and their novel polymorphisms in primary biliary cirrhosis. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain.

    Evidence for novel cannabinoid receptors. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Biochem Biophys Res Commun. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. A biosynthetic pathway for anandamide. The pharmacology of the cannabinoid system--a question of efficacy and selectivity. Structure and function of fatty acid amide hydrolase. Brain monoglyceride lipase participating in endocannabinoid inactivation.

    Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. CB 1 signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance.

    Modulation of the cannabinoid receptors by andrographolide attenuates hepatic apoptosis following bile duct ligation in rats with fibrosis. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Hepatic CB 1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma.

    The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Vasodilator mRNA levels are increased in the livers of portal hypertensive NO-synthase 3-deficient mice.

    Eur J Clin Invest. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB 1 and VR 1 receptors. Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration.

    Zaugg HE, Kyncl J. Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther. Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol. Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension.

    Polymyxin B binds to anandamide and inhibits its cytotoxic effect. Anandamide absorption by direct hemoperfusion with polymixin B-immobilized fiber improves the prognosis and organ failure assessment score in patients with sepsis. Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic rats. Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis.

    Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis. Renal sodium retention in preascitic cirrhosis: Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis. Systemic and portal hemodynamic effects of anandamide.

    Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Nat Clin Pract Gastroenterol Hepatol. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats.

    CB2 receptors as new therapeutic targets for liver diseases. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats.

    Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Anandamide induces cell death through lipid rafts in hepatic stellate cells. Leptin-regulated endocannabinoids are involved in maintaining food intake. Role of the endocannabinoid system in abdominal obesity and the implications for cardiovascular risk. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity.

    CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins.

    Peripherally acting CB1-receptor antagonist: Int J Obes Lond ; The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. Effects of the cannabinoid CB1 antagonist, rimonabant, on hepatic mitochondrial function in rats fed a high fat diet.

    Am J Physiol Endocrinol Metab. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice.

    Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways. CB1 receptor antagonist AVE affects primarily metabolic parameters independently of reduced food intake in Wistar rats. Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats.

    Anti-obesity effect of SR, a CB1 receptor antagonist, in diet-induced obese mice. Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Overfeeding rapidly induces leptin and insulin resistance. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.

    Deltatetrahydrocannabinol and glucose tolerance. Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. The emerging role of the endocannabinoid system in endocrine regulation and energy balance.

    Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Effects of rimonabant SR on fasting-induced hypothalamic-pituitary-adrenal axis and neuronal activation in lean and obese Zucker rats. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: Analysis of pooled 1 year data from four pivotal trials in overweight patients showed a significant decrease in serum alanine aminotransferase in patients under rimonabant, compared with placebo-treated individuals, suggesting a beneficial impact on fatty liver Van Gaal et al.

    Moreover, a computed tomography sub-study evaluated the distribution of fat depots and showed a reduction of liver steatosis in treated patients versus controls Despres et al. Overall, clinical data provide consistent evidences for a steatogenic role of endocannabinoids and CB 1 receptors in patients with NAFLD. Chronic alcohol abuse, a leading cause of liver-related morbi-mortality in Western countries, is associated with several patterns of liver injury presenting certain similarities to metabolic liver disease, ranging from isolated fatty liver to alcoholic hepatitis, cirrhosis and hepatocellular carcinoma Mandayam et al.

    Compelling evidences indicate that resident hepatic macrophages Kupffer cells play a key role in the initiation of alcoholic liver disease Mandrekar and Szabo, The currently accepted model stipulates that alcohol-induced enhancement of gut permeability increases translocation of bacterial liposaccharide LPS -endotoxin to the liver. Alcohol also sensitizes Kupffer cells to LPS by increasing oxidative stress, and primed Kupffer cells respond to LPS by polarization towards a pro-inflammatory M1 phenotype, characterized by up-regulation of a number of pro-inflammatory mediators, including cytokines and chemokines, as well as their cognate receptors Mandrekar and Szabo, Mice fed an ethanol diet were found to display a marked induction of hepatocyte CB 1 receptors and increased levels of 2-AG.

    The authors also showed that administration of rimonabant prevents the development of fatty liver elicited by chronic alcohol feeding. In addition, mice bearing an hepatocyte-specific deletion of CB 1 receptors were resistant to alcohol-induced fatty liver Jeong et al.

    The mechanism underlying CB 1 -mediated steatogenesis was ascribed to enhanced production of 2-AG by hepatic stellate cells, resulting in paracrine activation of CB 1 receptors in neighbouring hepatocytes with subsequent activation of lipogenesis and inhibition of fatty acid oxidation Jeong et al.

    Altogether, these results suggest that CB 1 antagonism may reduce the development of alcohol-induced fatty liver. Whether CB 1 inactivation might also interfere with the deleterious inflammatory reaction elicited by alcohol abuse remains to be investigated. Treatment of alcohol-induced liver disease should ideally reduce oxidative stress, macrophage activation and steatogenesis.

    In this respect, CB 2 receptors appear as attractive targets, given their well-demonstrated role in the control of innate immunity. We therefore investigated their impact in mice exposed to chronic alcohol feeding.

    We found that in alcohol-exposed mice, endogenous or exogenous activation of CB 2 receptors prevents the switch of Kupffer cells to a pro-inflammatory M1 phenotype and the accumulation of triglycerides in hepatocytes Louvet et al.

    In vitro experiments demonstrated that CB 2 receptor activation regulates macrophage polarization, by preventing the pro-inflammatory M1 response and inducing polarization towards an anti-inflammatory M2 phenotype Louvet et al. Moreover, there was a causal relationship between activation of macrophage CB 2 receptors and inhibition of hepatocyte steatogenesis. Indeed, mice lacking CB 2 receptors exhibited exacerbated steatosis, while animals treated with the CB 2 -selective agonist JWH showed no steatosis upon alcohol feeding Louvet et al.

    Because CB 2 receptors are not expressed in hepatocytes Deveaux et al. In vitro experiments demonstrated that preventing M1 polarization in CB 2 -stimulated macrophages reduces fat accumulation in hepatocytes Louvet et al. Altogether, these data demonstrate that CB 2 receptors display beneficial effects on alcohol liver disease by limiting hepatic inflammation and steatosis via autocrine and paracrine effects.

    This study identifies CB 2 receptor agonism as a potential promising approach in the management of alcohol-induced liver injury. Chronic liver diseases are characterized by prolonged liver injury resulting in the chronic activation of an altered wound-healing with progressive accumulation of fibrosis in the liver parenchyma, eventually leading to liver cirrhosis, portal hypertension and liver failure.

    Progression of fibrosis combines enhanced production of extracellular matrix by hepatic myofibroblasts and impaired matrix turnover Lotersztajn et al. Effective antifibrotic treatments are not available in humans as yet, and numerous efforts are directed at the development of liver-specific antifibrotic therapies.

    Studies from our lab have revealed the major impact of the endocannabinoid system in the regulation of liver fibrogenesis. Indeed, we found that CB 1 and CB 2 receptors are markedly up-regulated in cirrhotic liver samples, primarily in hepatic myofibroblasts, and demonstrated that endogenous activation of CB 1 receptors enhances fibrogenesis, whereas, conversely, stimulation of CB 2 receptors counteracts progression of fibrosis Julien et al.

    Antifibrogenic properties of CB 2 receptors were established using the carbon tetrachloride model, based on the findings that CB 2 -deficient mice show enhanced survival of liver fibrogenic cells resulting in increased fibrosis Julien et al.

    In line with our results, a subsequent study in rats with established cirrhosis showed that administration of the CB 2 -selective agonist JWH improves liver fibrosis, decreases the inflammatory infiltrate and reduces the density of hepatic myofibroblasts following increased apoptosis Munoz-Luque et al. Interestingly, antifibrogenic properties of CB 2 receptors have also been recently demonstrated in other organs, as shown in models of cardiac fibrosis Defer et al.

    The role of CB 1 receptors in liver fibrosis was examined in models of carbon tetrachloride or thioacetamide intoxication and in bile duct ligated animals. Administration of rimonabant to wild-type mice or genetic inactivation of CB 1 receptors were both associated with a significant reduction in fibrosis progression Teixeira-Clerc et al.

    Antifibrogenic properties of the CB 1 -selective antagonist were ascribed to antiproliferative and apoptotic properties of the compound in hepatic myofibroblasts.

    The antifibrogenic potential of CB 1 antagonism was also confirmed in a murine model of prolonged high fat feeding characterized by histological features of NASH including significant fibrosis DeLeve et al.

    Overall, these data strongly suggest that selective CB 2 agonists and peripherally restricted CB 1 antagonists may prove useful for the management of hepatic fibrosis. Aside from CB 1 - and CB 2 -mediated effects on liver fibrogenesis, endocannabinoids may also modulate the fibrogenic process by CB 1 - and CB 2 -independent pathways, although the latter are less fully characterized.

    The opposite effects of CB 1 and CB 2 receptors on experimental liver fibrosis raised the question as to the resulting effect in a clinical setting. We investigated this issue in a cohort of patients with chronic hepatitis C, by evaluating the impact of cannabis use on fibrosis progression. We identified daily cannabis smoking over the course of the disease as a strong independent predictor of fibrosis severity. Similar findings were reported in another cohort of patients Ishida et al.

    These data therefore suggest that CB 1 signalling dominates over CB 2 for exogenous cannabinoid ligands during chronic hepatitis C Hezode et al. In keeping, it has recently been shown that CB 1 expression is enhanced in the liver of patients with chronic hepatitis C, as compared with patients with chronic hepatitis B, a finding that was ascribed to induction of CB 1 expression by hepatitis C virus in experiments performed in an hepatocyte cell line infected with an hepatitis C virus subreplicon van der Poorten et al.

    Vasoregulatory effects of endocannabinoids have been extensively characterized. Several studies indicate that an enhanced peripheral CB 1 -dependent cannabinoid tone contributes to the pathogenesis of portal hypertension, via enhanced mesenteric vasodilation Batkai et al. In support of these data, administration of rimonabant to rats with established cirrhosis improves peripheral vascular resistance and blood pressure, thereby preventing the development of ascites Domenicali et al.

    Recent data also suggest that CB 1 -mediated stimulation of cardiomyocytes contribute to the cirrhotic cardiomyopathy associated with end-stage cirrhosis Gaskari et al. Recent data have shown that CB 2 receptors decrease the extent of liver injury in models of acute liver insult, as induced by ischaemia-reperfusion, thioacetamide or concanavalin-A Batkai et al. However, the mechanisms underlying these hepatoprotective effects remained unclear.

    We therefore investigated the impact of CB 2 receptor modulation on hepatocyte survival and liver regeneration in a model of acute hepatitis elicited by a single dose of carbon tetrachloride Teixeira-Clerc et al. We found that defective induction of inducible nitric oxide synthase in hepatocytes is responsible for enhanced apoptosis of these cells in CB 2 -deficient mice exposed to carbon tetrachloride, compared with wild-type littermates. In contrast, treatment of wild-type animals with the CB 2 -selective agonist JWH protected from the apoptotic effects of carbon tetrachloride Teixeira-Clerc et al.

    Results from CB 2 -deficient mice and mice treated with JWH also demonstrated that CB 2 receptors accelerate the regenerative response that follows acute liver injury in this model.

    Similar effects were also obtained in another model of liver regeneration, as induced by partial hepatectomy. The beneficial effects of CB 2 receptors on liver regeneration were related to an increased production of interleukin-6 from hepatic myofibroblasts, resulting in paracrine mitogenic effects on hepatocytes Teixeira-Clerc et al.

    This study therefore indicates that paracrine mechanisms originating from hepatic myofibroblasts account for beneficial effects of CB 2 receptors on hepatocyte survival and regeneration following an acute insult. Strinkingly, beneficial effects of CB 1 receptors on liver regeneration have also been recently reported Mukhopadhyay et al.

    Mice administered rimonabant or selectively lacking CB 1 receptors in hepatocytes displayed reduced liver regeneration, as reflected by a weak mitogenesis of hepatocytes Mukhopadhyay et al. Reduced proliferative activity of hepatocytes was the result of the inhibition of cell cycle proteins involved in mitotic progression, including forkhead-box M1 FoxM1 , a transcription factor that is also essential in the development of hepatocellular carcinoma.

    These data demonstrate that AEA acting on CB 1 receptors promotes liver regeneration; whether CB 1 receptors may also promote the development of hepatocellular carcinoma warrants further investigation. Over the past 10 years, the endocannabinoid system has emerged as a major player in the pathogenesis of liver diseases Figure 1. CB 1 receptors have been implicated in the pathogenesis of several lesions such as liver fibrogenesis, alcoholic and metabolic steatosis, or circulatory failure associated with cirrhosis.

    In contrast, stimulation of hepatic CB 2 receptors is emerging as an overall protective pathway with antifibrogenic properties and beneficial effects on liver inflammation, alcoholic fatty liver and hepatocyte survival and regeneration. Exciting therapeutic developments expected with the availability of CB 1 receptor antagonists have been put to a hold, due to the high incidence of central side effects of first generation compounds.

    Fortunately, CB 1 antagonists devoid of brain penetrance are increasingly being synthetized and initial results suggest that they exhibit beneficial effects expected from previous studies. The clinical development of CB 2 -selective agonists is also eagerly awaited.

    Role of the endocannabinoid system in the progression of chronic liver diseases: In western countries, prevailing causes of cirrhosis include chronic alcohol consumption, hepatitis C virus and obesity.

    Liver disease progression show common sequence of events whatever the origin. Studies over the last few years have shown that cannabinoid receptors [cannabinoid receptor 1 CB 1 and cannabinoid receptor 2 CB 2 ] and their endogenous ligands are highly up-regulated during chronic liver disease and affect multiple common steps, including steatosis, hepatocyte injury and inflammation steatohepatitis , fibrosis and liver regeneration. National Center for Biotechnology Information , U.

    Journal List Br J Pharmacol v. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Chronic liver diseases represent a major health problem due to cirrhosis and its complications.

    The endocannabinoid system Cannabis Sativa has a long-standing history of recreational and therapeutic use, starting over years ago. Pharmacomodulation of cannabinoid receptors Cannabinoid receptor 1 antagonists have undergone clinical development for the management of obesity, in light of their beneficial effect on food intake and energy expenditure.

    The hepatic cannabinoid system Basal hepatic expression of cannabinoid receptors is faint, with low levels of CB 2 receptors in Kupffer cells and of CB 1 receptors in endothelial cells and hepatocytes.

    CB 1 receptors promote metabolic steatosis and insulin resistance A large body of evidence has demonstrated that administration of CB 1 antagonists to obese animals reduces food intake and increases energy expenditure, thereby inducing weight loss Mallat and Lotersztajn, Pro-inflammatory effects of CB 2 receptors in fat tissue participate to the pathogenesis of NAFLD It is well established that low grade adipose tissue inflammation associated with obesity is a key determinant in the pathogenesis of insulin resistance and NAFLD Tilg and Moschen, Alcoholic liver disease Chronic alcohol abuse, a leading cause of liver-related morbi-mortality in Western countries, is associated with several patterns of liver injury presenting certain similarities to metabolic liver disease, ranging from isolated fatty liver to alcoholic hepatitis, cirrhosis and hepatocellular carcinoma Mandayam et al.

    CB 1 antagonism prevents the development of alcohol-induced fatty liver Jeong et al. CB 2 receptor activation reduces alcohol-induced liver inflammation and fatty liver Treatment of alcohol-induced liver disease should ideally reduce oxidative stress, macrophage activation and steatogenesis.

    Opposite effects of CB 1 and CB 2 receptors on liver fibrogenesis Chronic liver diseases are characterized by prolonged liver injury resulting in the chronic activation of an altered wound-healing with progressive accumulation of fibrosis in the liver parenchyma, eventually leading to liver cirrhosis, portal hypertension and liver failure. Antifibrogenic properties of CB 2 receptors Antifibrogenic properties of CB 2 receptors were established using the carbon tetrachloride model, based on the findings that CB 2 -deficient mice show enhanced survival of liver fibrogenic cells resulting in increased fibrosis Julien et al.

    Profibrogenic effects of CB 1 receptors The role of CB 1 receptors in liver fibrosis was examined in models of carbon tetrachloride or thioacetamide intoxication and in bile duct ligated animals. Receptor-independent effects of endocannabinoids on liver fibrogenesis Aside from CB 1 - and CB 2 -mediated effects on liver fibrogenesis, endocannabinoids may also modulate the fibrogenic process by CB 1 - and CB 2 -independent pathways, although the latter are less fully characterized.

    Clinical data The opposite effects of CB 1 and CB 2 receptors on experimental liver fibrosis raised the question as to the resulting effect in a clinical setting. The endocannabinoid system as a mediator of extrahepatic complications of cirrhosis Vasoregulatory effects of endocannabinoids have been extensively characterized.

    Protective effects of cannabinoid receptors on liver injury and regeneration Recent data have shown that CB 2 receptors decrease the extent of liver injury in models of acute liver insult, as induced by ischaemia-reperfusion, thioacetamide or concanavalin-A Batkai et al. Conclusion Over the past 10 years, the endocannabinoid system has emerged as a major player in the pathogenesis of liver diseases Figure 1.

    Open in a separate window. Conflicts of interest The authors have no conflict of interest. Click here to view. Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice.

    Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. A novel peripherally restricted cannabinoid receptor antagonist, AM, reduces food intake and body weight, but does not cause malaise, in rodents.

    Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes Lond ; Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase. Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis.

    Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. Targeting the endocannabinoid system: Nat Rev Drug Discov. The endocannabinoid system and its therapeutic exploitation. Cannabinoid type 1 receptor antagonism delays ascites formation in rats with cirrhosis. Activation of the peripheral endocannabinoid system in human obesity.

    Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids:

    The endocannabinoid system and liver diseases.

    Hence, hepatic cannabinoid receptor 2 (CB2) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and. Over the last decade, the endocannabinoid system has emerged as a pivotal mediator of acute and chronic liver injury, with the description of the role of CB1. Hence, hepatic cannabinoid receptor 2 (CB2) receptors display beneficial effects on fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis.

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