Cannabinoid‐2 receptor mediates protection against hepatic ischemia/reperfusion injury

Bátkai, Sándor; Osei‐Hyiaman, Douglas; Pān, Hào; El-Assal, Osama N.; Rajesh, Mohanraj; Mukhopadhyay, Partha; Hong, Feng; Harvey−White, Judith; Jafri, Anjum; Haskó, György; Huffman, John W.; Gao, Bin; Kunos, George; Pacher, Pál

doi:10.1096/fj.06-7451com

Cited by 221 publications

(306 citation statements)

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“…This suggests that 2-AG may stimulate the CB2 receptor, which is expressed on immune cells, including Kupffer cells, and has a general anti-inflammatory action (38,39). In liver, CB2 receptor agonists protect against ischemia/reperfusion injury by attenuating oxidative stress and inflammatory response (40,41). In man, CB2 receptor agonists reduce inflammation and fibrosis in patients with chronic liver disease (42).…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal and Microsomal Lipid Pathways Associated with Resistance to Hepatic Steatosis and Reduced Pro-inflammatory State

Hall

Poussin

Velagapudi

et al. 2010

Journal of Biological Chemistry

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Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and ␤-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal ␤-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower proinflammatory state as determined by lower plasma levels and IL-1␤ and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal ␤-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state.The current view of obesity-associated metabolic deregulations proposes that excessive accumulation of fat in adipose tissue initiates an inflammatory reaction characterized by cytokine production by adipocytes and infiltrating leukocytes (1, 2). This leads to the development of insulin resistance in adipocytes and increased release of free fatty acids. Secreted cytokines and free fatty acids then induce insulin resistance in muscle and liver, through activation of serine/threonine kinases that phosphorylate essential signaling proteins such as the insulin receptor or its main substrates IRS1 and IRS2 (3). In the liver, insulin resistance leads to unrestrained glucose production causing hyperglycemia. However, insulin still normally activates the lipogenic transcription factor SREBP-1c leading to hepatosteatosis, increased secretion of VLDL, and elevated plasma triglycerides (4). Therefore, there is a correlation between the degree of inflammation in the adipose tissue and liver fat content and insulin resistance (5), and studies in human have demonstrated a correlation between the level of fat accumulation in the liver and various parameters of the metabolic syndrome (6, 7).Changes in liver metaboli...

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Section: Discussionmentioning

confidence: 99%

Peroxisomal and Microsomal Lipid Pathways Associated with Resistance to Hepatic Steatosis and Reduced Pro-inflammatory State

Hall

Poussin

Velagapudi

et al. 2010

Journal of Biological Chemistry

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“…and a midline laparotomy incision was performed to expose the liver of anesthesized mice as described. 33,34 The hepatic artery and the portal vein were clamped using microaneurysm clamps. This model results in segmental (70%) hepatic ischemia.…”

Section: Animals Hepatic I/r Protocol and Histological Analysismentioning

confidence: 99%

“…Other materials and methods not described here were performed as previously described. 23,29,30,33,34 …”

Section: Data Processing and Statistical Analysismentioning

confidence: 99%

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

et al. 2008

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SummaryBackground & Aims-Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively-modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively-modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin MnTMPyP on oxidatively-modified proteins and their functions.

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“…In addition to a wide range of primarily CB 1 receptor-mediated physiological effects on the central nervous system, different cannabinoid ligands have been reported to modulate immune responses (14). In particular, CB 2 receptor ligands have been shown to inhibit inflammation and edema formation (15), exhibit analgesic effects (16), and play a protective role in hepatic ischemia-reperfusion injury (17). In the gastrointestinal tract, CB 2 receptor agonists have been shown to prevent experimental colitis by reducing inflammation (18).…”

mentioning

confidence: 99%

Beta-caryophyllene is a dietary cannabinoid

Gertsch

Leonti

Raduner

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

724

583

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The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB1) and CB2 receptors. Although the CB1 receptor is responsible for the psychomodulatory effects, activation of the CB2 receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E) Cannabis ͉ CB2 cannabinoid receptor ͉ foodstuff ͉ inflammation ͉ natural product P lant essential oils are typically composed of volatile aromatic terpenes and phenylpropanoids. These lipophilic volatiles freely cross cellular membranes and serve various ecological roles, like plant-insect interactions (1, 2). The sesquiterpene (E)-␤-caryophyllene [(E)-BCP] (Fig. 1) is a major plant volatile found in large amounts in the essential oils of many different spice and food plants, such as oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) and black pepper (Piper nigrum L.) (3-5). In nature, (E)-BCP is usually found together with small quantities of its isomers (Z)-␤-caryophyllene [(Z)-BCP or isocaryophyllene] and ␣-humulene (formerly ␣-caryophyllene) or in a mixture with its oxidation product, BCP oxide (Fig. 1). Because of its weak aromatic taste, (E)-BCP is commercially used as a food additive and in cosmetics (6). (E)-BCP is also a major component (up to 35%) in the essential oil of Cannabis sativa L (7). Although Cannabis contains Ͼ400 different secondary metabolites, including Ͼ65 cannabinoid-like natural products, only ⌬ 9 -tetrahydrocannabinol (THC), ⌬ 8 -tetrahydrocannabinol, and cannabinol have been reported to activate cannabinoid receptor types 1 (CB 1 ) and 2 (CB 2 ) (8). Here, we show that the essential oil component (E)-BCP selectively binds to the CP55,940 binding site (i.e., THC binding site) in the CB 2 receptor, leading to cellular activation and antiinflammatory effects. CB 1 and CB 2 cannabinoid receptors are GTP-binding protein (G protein) coupled receptors that were first cloned in the early 1990s (9, 10). Although the CB 1 receptor is expressed in the central nervous system and in the periphery, the CB 2 receptor is primarily found in peripheral tissues (11). In vivo, CB receptors are activated by arachidonic acid-derived endocannabinoids, such as 2-arachidonoyl ethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (12, 13). In addition to a wide range of primarily CB 1 receptor-mediated physiological effects on the central nervous system, different cannabinoid ligands have been reported to modulate immune responses (14). In particular, CB 2 receptor ligands have been shown to inhibit inflammation and edema formation (15), exhibit analgesic effects (16), and play a protective role in hepatic ischemia-reperfusion injury (17). In the gastrointestinal tract, CB 2 receptor agonists have been shown to prevent experimental colitis by reducing inflammation (18). Moreover, the CB 2 receptor has been described as a potential ...

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Cannabinoid‐2 receptor mediates protection against hepatic ischemia/reperfusion injury

Cited by 221 publications

References 69 publications

Peroxisomal and Microsomal Lipid Pathways Associated with Resistance to Hepatic Steatosis and Reduced Pro-inflammatory State

Peroxisomal and Microsomal Lipid Pathways Associated with Resistance to Hepatic Steatosis and Reduced Pro-inflammatory State

Oxidative Inactivation of Key Mitochondrial Proteins Leads to Dysfunction and Injury in Hepatic Ischemia Reperfusion

Beta-caryophyllene is a dietary cannabinoid

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