Journal article
A Critical Role for Ceramide Synthase 2 in Liver Homeostasis II. INSIGHTS INTO MOLECULAR CHANGES LEADING TO HEPATOPATHY
Journal of Biological Chemistry, Vol.285(14), pp.10911-10923
Apr/2010
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 similar to 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.
Details
- Title
- A Critical Role for Ceramide Synthase 2 in Liver Homeostasis II. INSIGHTS INTO MOLECULAR CHANGES LEADING TO HEPATOPATHY
- Creators
- Yael Pewzner-Jung (null) - 972WIS_INST___112Ori Brenner (null) - The Weizmann Institute of ScienceSvantje Braun (null)Elad L. Laviad (null)Shifra Ben-Dor (null) - 972WIS_INST___113Ester Feldmesser (null) - 972WIS_INST___113Shirley Horn-Saban (null) - 972WIS_INST___113Daniela Amann Zalcenstein (null) - 972WIS_INST___971Calanit Raanan (null) - The Weizmann Institute of ScienceTamara Berkutzki (null)Racheli Erez Roman (null) - 972WIS_INST___112Oshrit Ben David (null) - 972WIS_INST___112Michal Levy (null)Dorin Holzman (null) - The Weizmann Institute of ScienceHyejung Park (null)Abraham Nyska (null)Alfred H. Merrill, Jr. (null)Anthony H. Futerman (null) - 972WIS_INST___112
- Resource Type
- Journal article
- Publication Details
- Journal of Biological Chemistry, Vol.285(14), pp.10911-10923; Apr/2010
- Number of pages
- 13
- Language
- English
- DOI
- https://doi.org/10.1074/jbc.M109.077610
- Grant note
- National Institutes of Health [GM076217]; Israel Science Foundation [1404/07]; Minerva FoundationThis work was supported, in whole or in part, by National Institutes of Health Grant GM076217. This work was also supported by Israel Science Foundation Grant 1404/07 and by The Minerva Foundation._ALMAME_DELIMITER_
- Record Identifier
- 993264938203596
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