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• W1970236413 abstract "Cannabinoid signaling by CB1 receptors drives fibrogenesis and fat accumulation in liver. A report in this issue of Cell Metabolism (Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar) now links hepatic stellate cells, a resident liver fibrogenic cell type, to the generation of steatosis through production of the endocannabinoid 2-arachidonoylglycerol (2-AG) after ethanol feeding, leading to paracrine stimulation of hepatocyte CB1 receptors. Cannabinoid signaling by CB1 receptors drives fibrogenesis and fat accumulation in liver. A report in this issue of Cell Metabolism (Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar) now links hepatic stellate cells, a resident liver fibrogenic cell type, to the generation of steatosis through production of the endocannabinoid 2-arachidonoylglycerol (2-AG) after ethanol feeding, leading to paracrine stimulation of hepatocyte CB1 receptors. For years, a fatty liver was typically considered an innocuous and transient consequence of alcohol ingestion, obesity, or occasionally prescription drugs. More recently, however, the metabolic and pathogenic costs of fat accumulation in liver have become increasingly apparent. Fat generates inflammatory signals and reactive oxygen species that can amplify liver injury and stimulate fibrosis, or scarring. In particular, induction of cytochrome P450 2E1 (CYP2E1) by ethanol is a critical response following chronic ethanol ingestion and in nonalcoholic fatty liver disease (NAFLD) that leads to enhanced generation of reactive oxygen species and liver injury (Dey and Cederbaum, 2006Dey A. Cederbaum A.I. Hepatology. 2006; 43: S63-S74Crossref PubMed Scopus (451) Google Scholar, Nieto et al., 2002Nieto N. Friedman S.L. Cederbaum A.I. J. Biol. Chem. 2002; 277: 9853-9864Crossref PubMed Scopus (154) Google Scholar). Even in “bland” steatosis due to alcohol, where inflammatory cells are lacking, early activation of resident fibrogenic cells (hepatic stellate cells) is already apparent (Reeves et al., 1996Reeves H.L. Burt A.D. Wood S. Day C.P. J. Hepatol. 1996; 25: 677-683Abstract Full Text PDF PubMed Scopus (131) Google Scholar). Thus, the main diseases characterized by hepatic steatosis—alcoholic fatty liver and NAFLD—are recognized as harbingers of worse disease to follow when liver insult is sustained. Additionally, the presence of fat in patients with hepatitis C (HCV) infection independently accelerates progression of fibrosis to cirrhosis, the end stage of sustained liver injury (Leandro et al., 2006Leandro G. Mangia A. Hui J. Fabris P. Rubbia-Brandt L. Colloredo G. Adinolfi L.E. Asselah T. Jonsson J.R. Smedile A. et al.Gastroenterology. 2006; 130: 1636-1642Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar). All of these hepatic conditions are highly pervasive and increasing worldwide. In this context, the findings of Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar reported in this issue of Cell Metabolism offer a clinically important new mechanism to explain fat accumulation in liver through a conspiracy of cell-cell interactions between neighboring cell types. With the recognition that fat accumulation contributes to disease, attention has turned toward understanding its pathogenesis. In particular, metabolic pathways regulating fat in liver have been closely scrutinized, with evidence of both enhanced lipogenesis and decreased lipolysis in diseases associated with steatosis. Adipokines, oxidant stress, and mitochondrial injury have been implicated as well (Albano, 2006Albano E. Proc. Nutr. Soc. 2006; 65: 278-290Crossref PubMed Scopus (400) Google Scholar). While these local metabolic factors have provided ample explanation for fat accumulation, they have focused primarily on the role of hepatocytes, the metabolic workhorse of liver, and not on potential contributions of other, nonparenchymal cell types, including hepatic macrophages (Kupffer cells), stellate cells, and sinusoidal endothelial cells. The study by Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar now convincingly implicates hepatic stellate cells as important paracrine mediators of steatosis in liver. Added to the burden of disease due to alcohol are additional morbidities conferred by other drugs of abuse, in particular cannabis, which is a risk factor for fibrosis progression in chronic liver disease due to HCV and possibly other etiologies (Hezode et al., 2005Hezode C. Roudot-Thoraval F. Nguyen S. Grenard P. Julien B. Zafrani E.S. Pawlotsky J.M. Dhumeaux D. Lotersztajn S. Mallat A. Hepatology. 2005; 42: 63-71Crossref PubMed Scopus (231) Google Scholar). These and related epidemiologic studies have coupled cannabinoids to the pathogenesis of liver disease, as underscored by a series of studies demonstrating that whereas the CB1 cannabinoid receptor is profibrogenic toward the activated hepatic stellate cell, the CB2 receptor has the opposite effect (Mallat et al., 2007Mallat A. Teixeira-Clerc F. Deveaux V. Lotersztajn S. Expert Opin. Ther. Targets. 2007; 11: 403-409Crossref PubMed Scopus (55) Google Scholar). Thus, the CB1 receptor antagonist rimonabant not only blunts the central effects of CB1 on appetite suppression but also has an independent effect in blocking hepatic fibrogenesis (Mallat et al., 2007Mallat A. Teixeira-Clerc F. Deveaux V. Lotersztajn S. Expert Opin. Ther. Targets. 2007; 11: 403-409Crossref PubMed Scopus (55) Google Scholar). At the same time, cannabinoids also promote the development of fatty liver, since CB1 stimulation in mice induces hepatic fatty acid synthesis whereas CB1 receptor knockout mice are resistant to diet-induced obesity (Osei-Hyiaman et al., 2005Osei-Hyiaman D. DePetrillo M. Pacher P. Liu J. Radaeva S. Batkai S. Harvey-White J. Mackie K. Offertaler L. Wang L. Kunos G. J. Clin. Invest. 2005; 115: 1298-1305Crossref PubMed Scopus (883) Google Scholar). Moreover, daily marijuana use is a risk factor for steatosis in HCV-infected individuals (Hezode et al., 2008Hezode C. Zafrani E.S. Roudot-Thoraval F. Costentin C. Hessami A. Bouvier-Alias M. Medkour F. Pawlostky J.M. Lotersztajn S. Mallat A. Gastroenterology. 2008; 134: 432-439Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The mechanisms underlying cannabinoid-mediated steatosis have remained obscure, however. Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar have introduced a vital link in this chain connecting cannabinoids to the steatotic effects of ethanol, unearthing a surprising new role for hepatic stellate cells. These resident nonparenchymal cells are adjacent to hepatocytes and surround the hepatic vascular unit, or sinusoid, harboring a broad range of functions in normal and injured liver (Friedman, 2008Friedman S.L. Physiol. Rev. 2008; 88: 125-172Crossref PubMed Scopus (1829) Google Scholar). In liver injury, stellate cells undergo a characteristic “activation” into fibrogenic cells that secrete a range of cytokines, reactive oxygen species, and inflammatory mediators. Remarkably, the Jeong et al. study demonstrates that the endocannabinoid 2-arachidonoylglycerol (2-AG) is among those factors secreted by activated stellate cells during liver injury due to ethanol feeding. Furthermore, induction of endocannabinoids was restricted to 2-AG, since anandamide, another endogenous cannabinoid, was not elevated by ethanol. Although mouse models of ethanol administration do not recapitulate the full spectrum of inflammation and injury seen in human disease, they do elicit steatosis and oxidant stress, and thus the finding that ethanol feeding stimulates 2-AG levels is likely to be relevant to human alcoholic liver disease. On the other hand, 2-AG stimulation is not simply a direct effect of alcohol or its metabolites on stellate cells, since ethanol did not induce 2-AG production in cultured stellate cells. Rather, a more likely pathway—and one that should be tested in future studies—is one wherein ethanol metabolism by hepatocytes generates paracrine signals that drive 2-AG synthesis by stellate cells. Paracrine stimulation of CB1 receptor signaling in hepatocytes by 2-AG derived from neighboring stellate cells is a major finding of the Jeong et al. study. The importance of hepatocyte responses to 2-AG was confirmed first by using rimonabant to attenuate CB1 signaling and thereby block steatosis in vivo, and then by assessing the effects of ethanol in mice selectively deficient in CB1 receptors only in hepatocytes. These liver-specific CB1 receptor knockout mice are particularly useful in that they avoid any confounding effects of CB1 signaling in the central nervous system, where the receptor is far more abundantly expressed than in liver. Animals with hepatocyte-specific deletion of CB1 receptors were resistant to the steatotic effects of ethanol feeding. Moreover, induction of the lipogenic mediators sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS) was blunted and activity of carnitine palmitoyltransferase 1 (CPT1) was no longer inhibited in mice with either global or hepatocyte-specific deletion of CB1 receptors. It would be informative to determine whether CYP2E1 expression is additionally affected by CB1 loss, as this could attenuate liver injury by reducing oxidative stress. The intriguing findings of Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar introduce a new paradigm in our understanding of fatty liver and its potential attenuation by available pharmacological agents. Paracrine signaling by a nonparenchymal cell to modulate hepatocyte responses may be relevant to a number of intermediary pathways apart from fat metabolism, including homeostasis of carbohydrates, proteins, vitamins, and metals (especially iron and copper). Effects of Kupffer cells and sinusoidal endothelial cells as other sources of paracrine stimuli should also be considered in order to dissect whether these effects derive exclusively from stellate cells, although this seems unlikely. It is possible, but still unproven, that the paracrine pathway described by Jeong et al., 2008Jeong W.-i. Osei-Hyiaman D. Park O. Liu J. Bátkai S. Mukhopadhyay P. Horiguchi N. Harvey-White J. Marsicano G. Lutz B. et al.Cell Metab. 2008; 7 (this issue): 227-235Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar could contribute to fatty liver due to etiologies other than alcohol, especially NAFLD. In summary, the uncovering of paracrine cannabinoid signaling as a determinant of hepatic steatosis unveils exciting new possibilities for both understanding and regulating fat accumulation in liver. Combined with data implicating cannabinoids in hepatic fibrogenesis, this pathway is assuming a central role in the regulation of hepatic metabolism, injury, and fibrosis. Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty LiverJeong et al.Cell MetabolismMarch 05, 2008In BriefAlcohol-induced fatty liver, a major cause of morbidity, has been attributed to enhanced hepatic lipogenesis and decreased fat clearance of unknown mechanism. Here we report that the steatosis induced in mice by a low-fat, liquid ethanol diet is attenuated by concurrent blockade of cannabinoid CB1 receptors. Global or hepatocyte-specific CB1 knockout mice are resistant to ethanol-induced steatosis and increases in lipogenic gene expression and have increased carnitine palmitoyltransferase 1 activity, which, unlike in controls, is not reduced by ethanol treatment. Full-Text PDF Open Archive" @default.
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• W1970236413 title "Cannabinoids Provoke Alcoholic Steatosis through a Conspiracy of Neighbors" @default.
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