Endocannabinoids and liver disease – review

Gabbay, Ezra; Avraham, Yosefa; Ilan, Yaron; Israeli, Eran; Berry, Elliot M.

doi:10.1111/j.1478-3231.2005.01180.x

Cited by 35 publications

(45 citation statements)

References 63 publications

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“…There are currently two known subtypes termed CB 1 and CB 2 . CB 1 receptors (CB1R) are expressed at high levels in the brain but are also present at much lower levels in peripheral tissues (10,40). The activation of hepatic CB1R was shown to stimulate expression of SREBP-1c and its downstream target genes and promote de novo lipid synthesis (29).…”

Section: Discussionmentioning

confidence: 99%

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism

Park

Lee

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Oh KJ, Park J, Lee SY, Hwang I, Kim JB, Park TS, Lee HJ, Koo SH. Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism. Am J Physiol Endocrinol Metab 300: E624-E632, 2011. First published January 11, 2011; doi:10.1152/ajpendo.00502.2010.-Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPK␣ and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPAR␣, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPKdependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPK␣ phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPAR␣ transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.adenosine 5=-monophosphate-activated protein kinase; sterol regulatory element-binding protein; peroxisome proliferator-activated receptor-␣ ATYPICAL ANTIPSYCHOTIC DRUGS (AAPDs) have been used in the pharmacological treatment of schizophrenia (1). Although the second-generation AAPDs are much potent than the classical antipsychotics, treatment of AAPDs could cause troublesome side effects, such as obesity, insulin resistance, dyslipidemia, abnormal glucose tolerance, and diabetes (5,11,23,36).Patients taking stable doses of clinically assigned olanzapine (OLZ) or clozapine (CLZ) have significantly higher fat mass, plasma insulin, glucose, triglyceride, and cholesterol levels (4, 5, 28). However, the exact molecular mechanism by which AAPDs lead to metabolic disorder remains unknown.Dysregulation of lipid metabolism is a critical instigator for the metabolic disorder. Recently, it has been reported that antipsychotic drugs such as OLZ and CLZ activate maturation of sterol regulator...

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Section: Discussionmentioning

confidence: 99%

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism

Park

Lee

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Recent evidence indicates that the endocannabinoid system plays an important role in the control of gastrointestinal motility and secretion both under physiological conditions and in various gastrointestinal disorders (reviewed in Pertwee, 2001;Pinto et al, 2002a,b;Di Carlo and Izzo, 2003 Massa et al, 2005). Unexpectedly, recent data also implicate endocannabinoids and their receptors in several aspects of acute and chronic liver disease, including hemodynamic changes, modulation of inflammatory processes, fibrosis, and altered brain function (reviewed in Gabbay et al, 2005;Jimenez, 2005).…”

Section: G Gastrointestinal and Liver Disordersmentioning

confidence: 99%

“…Interestingly, in animal models of acute hepatic failureinduced encephalopathy, both 2-AG and SR141716 have been reported to exert beneficial effects on neurological and cognitive function (Gabbay et al, 2005;Avraham et al, 2006). Cannabinoids may also be beneficial in intractable cholestatic pruritus (Neff et al, 2002), which is associated with severe forms of liver disease, presumably by increasing the nociceptive threshold (Gingold and Bergasa, 2003).…”

Section: G Gastrointestinal and Liver Disordersmentioning

confidence: 99%

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

2006

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“…[8][9][10][11][12][13][14][15]). The synthetic and natural ligands (the latter called endocannabinoids: arachidonoyl ethanolamide or anandamide and 2-arachidonoylglycerol) of cannabinoid (CB) receptors exert various antiinflammatory and neuroprotective [16][17][18] effects by inhibiting the generation and release of proinflammatory cytokines and mediators (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis

Rajesh¹,

Pān²,

Mukhopadhyay³

et al. 2007

Journal of Leukocyte Biology

130

142

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In this study, we have investigated the role of the cannabinoid CB 2 (CB 2 ) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB 2 receptor in TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB 2 receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-α, MIP-1α, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-α-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB 2 receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB 2 receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.

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Endocannabinoids and liver disease – review

Cited by 35 publications

References 63 publications

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis

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