Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice

Zongxian Cao, Melinda M. Mulvihill, Partha Mukhopadhyay, Huan Xu, Katalin Erdélyi, Enkui Hao, Eileen Holovac, G. Haskó, Benjamin F. Cravatt, Daniel K. Nomura, Pál Pacher

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Abstract

Background & Aims: The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. Methods: We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll-/- mice, fatty acid amide hydrolase-/- mice, and in cannabinoid receptor type 1-/- (CB1-/-) and cannabinoid receptor type 2-/- (CB 2-/-). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. Results: Wild-type mice given JZL184 and Mgll-/- mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB 2 and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl 4. Conclusions: MAGL modulates hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat conditions that expose the liver to oxidative stress and inflammatory damage.

Original languageEnglish
JournalGastroenterology
Volume144
Issue number4
DOIs
Publication statusPublished - Apr 2013

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Monoacylglycerol Lipases
Endocannabinoids
Eicosanoids
Liver
Wounds and Injuries
Cannabinoid Receptors
Oxidative Stress
Inflammation
Reperfusion Injury
Reperfusion
Hepatocytes
Ischemia
Galactosamine
Kupffer Cells
Arachidonic Acid
Biochemistry
Prostaglandins
Lipopolysaccharides
Molecular Biology

Keywords

  • Eicosanoid Production
  • Endocannabinoid Signaling
  • Mouse Model
  • Surgery

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Cao, Z., Mulvihill, M. M., Mukhopadhyay, P., Xu, H., Erdélyi, K., Hao, E., ... Pacher, P. (2013). Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology, 144(4). https://doi.org/10.1053/j.gastro.2012.12.028

Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. / Cao, Zongxian; Mulvihill, Melinda M.; Mukhopadhyay, Partha; Xu, Huan; Erdélyi, Katalin; Hao, Enkui; Holovac, Eileen; Haskó, G.; Cravatt, Benjamin F.; Nomura, Daniel K.; Pacher, Pál.

In: Gastroenterology, Vol. 144, No. 4, 04.2013.

Research output: Contribution to journalArticle

Cao, Z, Mulvihill, MM, Mukhopadhyay, P, Xu, H, Erdélyi, K, Hao, E, Holovac, E, Haskó, G, Cravatt, BF, Nomura, DK & Pacher, P 2013, 'Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice', Gastroenterology, vol. 144, no. 4. https://doi.org/10.1053/j.gastro.2012.12.028
Cao, Zongxian ; Mulvihill, Melinda M. ; Mukhopadhyay, Partha ; Xu, Huan ; Erdélyi, Katalin ; Hao, Enkui ; Holovac, Eileen ; Haskó, G. ; Cravatt, Benjamin F. ; Nomura, Daniel K. ; Pacher, Pál. / Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. In: Gastroenterology. 2013 ; Vol. 144, No. 4.
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AU - Xu, Huan

AU - Erdélyi, Katalin

AU - Hao, Enkui

AU - Holovac, Eileen

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