title: A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy.
abstract: We have generated a mouse that cannot synthesize very long acyl chain (C22-C24) ceramides (Pewzner-Jung, Y., Park, H., Laviad, E. L., Silva, L. C., Lahiri, S., Stiban, J., Erez-Roman, R., Brugger, B., Sachsenheimer, T., Wieland, F. T., Prieto, M., Merrill, A. H., and Futerman, A. H. (2010) J. Biol. Chem. 285, 10902-10910) due to ablation of ceramide synthase 2 (CerS2). As a result, significant changes were observed in the sphingolipid profile of livers from these mice, including elevated C16-ceramide and sphinganine levels. We now examine the functional consequences of these changes. CerS2 null mice develop severe nonzonal hepatopathy from about 30 days of age, the age at which CerS2 expression peaks in wild type mice, and display increased rates of hepatocyte apoptosis and proliferation. In older mice there is extensive and pronounced hepatocellular anisocytosis with widespread formation of nodules of regenerative hepatocellular hyperplasia. Progressive hepatomegaly and noninvasive hepatocellular carcinoma are also seen from approximately 10 months of age. Even though CerS2 is found at equally high mRNA levels in kidney and liver, there are no changes in renal function and no pathological changes in the kidney. High throughput analysis of RNA expression in liver revealed up-regulation of genes associated with cell cycle regulation, protein transport, cell-cell interactions and apoptosis, and down-regulation of genes associated with intermediary metabolism, such as lipid and steroid metabolism, adipocyte signaling, and amino acid metabolism. In addition, levels of the cell cycle regulator, the cyclin dependent-kinase inhibitor p21(WAF1/CIP1), were highly elevated, which occurs by at least two mechanisms, one of which may involve p53. We propose a functional rationale for the synthesis of sphingolipids with very long acyl chains in liver homeostasis and in cell physiology.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.forename: Ori
authors.initials: O
authors.lastname: Brenner
authors.forename: Svantje
authors.initials: S
authors.lastname: Braun
authors.forename: Elad L
authors.initials: EL
authors.lastname: Laviad
authors.forename: Shifra
authors.initials: S
authors.lastname: Ben-Dor
authors.forename: Ester
authors.initials: E
authors.lastname: Feldmesser
authors.forename: Shirley
authors.initials: S
authors.lastname: Horn-Saban
authors.forename: Daniela
authors.initials: D
authors.lastname: Amann-Zalcenstein
authors.forename: Calanit
authors.initials: C
authors.lastname: Raanan
authors.forename: Tamara
authors.initials: T
authors.lastname: Berkutzki
authors.forename: Racheli
authors.initials: R
authors.lastname: Erez-Roman
authors.forename: Oshrit
authors.initials: O
authors.lastname: Ben-David
authors.forename: Michal
authors.initials: M
authors.lastname: Levy
authors.forename: Dorin
authors.initials: D
authors.lastname: Holzman
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006529:Hepatomegaly / Q000201:enzymology / Q000473:pathology*; D006706:Homeostasis; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008111:Liver Function Tests; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D008055:Lipids; D012333:RNA, Messenger; D010088:Oxidoreductases; C108138:dihydroceramide desaturase