title: Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization.
abstract: Very long chain (C22-C24) ceramides are synthesized by ceramide synthase 2 (CerS2). A CerS2 null mouse displays hepatopathy because of depletion of C22-C24 ceramides, elevation of C16-ceramide, and/or elevation of sphinganine. Unexpectedly, CerS2 null mice were resistant to acetaminophen-induced hepatotoxicity. Although there were a number of biochemical changes in the liver, such as increased levels of glutathione and multiple drug-resistant protein 4, these effects are unlikely to account for the lack of acetaminophen toxicity. A number of other hepatotoxic agents, such as d-galactosamine, CCl4, and thioacetamide, were also ineffective in inducing liver damage. All of these drugs and chemicals require connexin (Cx) 32, a key gap junction protein, to induce hepatotoxicity. Cx32 was mislocalized to an intracellular location in hepatocytes from CerS2 null mice, which resulted in accelerated rates of its lysosomal degradation. This mislocalization resulted from the altered membrane properties of the CerS2 null mice, which was exemplified by the disruption of detergent-resistant membranes. The lack of acetaminophen toxicity and Cx32 mislocalization were reversed upon infection with recombinant adeno-associated virus expressing CerS2. We establish that Gap junction function is compromised upon altering the sphingolipid acyl chain length composition, which is of relevance for understanding the regulation of drug-induced liver injury.
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Woo-Jae
authors.initials: WJ
authors.lastname: Park
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Racheli
authors.initials: R
authors.lastname: Erez-Roman
authors.forename: Aviram
authors.initials: A
authors.lastname: Kogot-Levin
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Bame
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002518:Ceramides / Q000096:biosynthesis* / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D005688:Galactosamine / Q000633:toxicity; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000097002:Gap Junction beta-1 Protein
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D002251:Carbon Tetrachloride; D002518:Ceramides; D017630:Connexins; D005688:Galactosamine; D005978:Glutathione; D051049:Sphingosine N-Acyltransferase; D000097002:Gap Junction beta-1 Protein; C580723:Cers2 protein, mouse
keywords: Ceramide; Ceramide Synthase; Drug Resistance; Liver Injury; Membrane Lipids; Sphingolipid
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