Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

Patsenker, E.; Stoll, Matthias; Millonig, Gunda; Agaimy, Abbas; Wissniowski, TT; Schneider, V.; Mueller, Sebastian; Brenneisen, Rudolf; Seitz, Helmut K.; Ocker, Matthias; Stickel, Felix

doi:10.2119/molmed.2011.00149

Cited by 72 publications

(58 citation statements)

References 48 publications

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“…The main direct evidence for intracellular localization of CB 1 Rs in hepatocytes is from immunostaining experiments with rodent and human liver tissue samples. Although this does not provide definitive proof for intracellular localization of upregulated hepatic CB 1 Rs, due to the absence of information from classical biochemical tests (such as preparing heavy organelle, light organelle and cytosolic fractions from cells by directed Förster resonance energy transfer assays on binding partners) or by ultrastructural analyses using immune‐electron microscopy, the pattern of staining in the published images, particularly in articles by van der Poorten et al .…”

Section: Cytosolic Localization Functional Activity and Hyperactivatmentioning

confidence: 99%

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

Cooper

Regnell

2013

Brit J Clinical Pharma

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The cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. The CB1R is also expressed peripherally, where its effects include promotion of liver fat accumulation, which consumes ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blockade of hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitizing effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis. Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and bodyweight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may be effective in treating inflammatory liver disease, such as non-alcoholic steatohepatitis, reducing the likelihood of disease progression to cirrhosis or cancer. Hepatic energy state and its effects on food intakeThe cellular energy state is defined by adenine nucleotide levels. Healthy cells maintain a ratio of ATP to ADP of the order of 10:1. Cellular concentrations of ADP typically remain constant, while ATP and AMP levels deviate in reciprocal directions [1].Hepatic energy state influences food intake [2, 3]. For instance, infusion of various lipids and carbohydrates into the hepatic portal vein of rodents was found to suppress food intake more effectively than administration of the same nutrients into the jugular vein [2]. Supporting results were found when injecting the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) into the portal vein. In the liver, 2,5-AM is phosphorylated at the 1 and 6 positions, but not metabolized further, thus lowering the levels of free intracellular phosphates, which reduces the generation of ATP, whilst increasing its degradation by disinhibiting adenosine deaminase. The net result is a lower hepatocellular ATP concentration, which increases feeding [4]. Pretreatment with sodium phosphate prevents the decrease in liver ATP levels and the increase in feeding [5]. Administration of the amino-acid analogue L-ethionin...

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Section: Cytosolic Localization Functional Activity and Hyperactivatmentioning

confidence: 99%

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

Cooper

Regnell

2013

Brit J Clinical Pharma

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“…The median age was 26 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) The CD, CV, HEX and CCT data for both groups are shown in Table 1. The mean CD was 2900±211 cells/mm 2 in the cannabinoid group and 3097±214 cells/mm 2 in the control group (p< 0.01).…”

Section: Resultsmentioning

confidence: 99%

“…The activation of CB1 receptors has been shown to have toxic effect by amplifying oxidative stress, mitogen-activated protein kinase (MAPK) activation and cell death, and the subsequent inflammatory response (20). The inactivation of CB1 receptors has been shown to have protective effect (21). On the other hand studies reported that when CB2 receptors activated protective effect became marked by the antiinflammatory actions (22,23).…”

Section: J U S T a C C E P T E Dmentioning

confidence: 99%

Corneal endothelial changes in long-term cannabinoid users

Polat

Cumurcu

et al. 2017

Cutaneous and Ocular Toxicology

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“…Despite that the exact interactions between CBR signaling, PI3K pathway, and pathogenic fibrosis remain to be elucidated, recent studies found that the CB 2 R agonist is able to degrade the extracellular matrix through the activation of MMPs [46]. In addition, the CB 1 R antagonist has also been shown to protect against alcoholic liver fibrosis via downregulating TIMP-1 [47]. As to peritoneal fibrosis, Kim et al [48] had shown that high glucose decreased MMP and increased TIMP expression in cultured mesothelial cells, but the participating roles of the CBR signaling system were not examined in their study.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptors as Therapeutic Targets for Dialysis-Induced Peritoneal Fibrosis

et al. 2013

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Background: Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. Methods: We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB₁R) antagonist and the type 2 CBR (CB₂R) agonist. Results: In the methylglyoxal model, both intraperitoneal CB₁R antagonist (AM281) and CB₂R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB₁R antagonist was able to alleviate TGF-β₁-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. Conclusions: Intraperitoneal administration of CBR ligands (CB₁R antagonist and CB₂R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.

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Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

Cited by 72 publications

References 48 publications

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake

Corneal endothelial changes in long-term cannabinoid users

Cannabinoid Receptors as Therapeutic Targets for Dialysis-Induced Peritoneal Fibrosis

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