title: Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice.
abstract: OBJECTIVE
  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(-/-) (CB2-/-). 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 CB2 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 CCl4.
  
  
  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.
authors.affiliation: Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Mulvihill
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdélyi
authors.forename: Enkui
authors.initials: E
authors.lastname: Hao
authors.forename: Eileen
authors.initials: E
authors.lastname: Holovac
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress; D010880:Piperidines / Q000494:pharmacology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D052117:Benzodioxoles; D015777:Eicosanoids; D063388:Endocannabinoids; D018836:Inflammation Mediators; C534333:JZL 184; D010880:Piperidines; D017382:Reactive Oxygen Species; D008994:Monoacylglycerol Lipases