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Short-chain ceramide regulates hepatic methionine adenosyltransferase expression

AuthorsFrago, Laura M.; Pañeda, Covadonga; Fabregat, Isabel; Varela-Nieto, Isabel
Issue Date2001
CitationJournal of Hepatology 34(2): 192-201 (2001)
Abstract[Background]: The metabolism of methionine plays an important role in regulating hepatic cellular function. Methionine adenosyltransferase (MAT) is the enzyme that catalyses the biosynthesis of S-adenosylmethionine (AdoMet) from ATP and methionine. Liver-specific MAT I/III levels are down-regulated in the regenerating rat liver after partial hepatectomy. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are two cytokines fundamental for liver regeneration. TNF-α stimulates sphingomyelin metabolism and ceramide generation in a variety of cell systems. [Aims]: The role of exogenous cell-permeable ceramide in modifying MAT I/III mRNA levels and its association with TNF-α and IL-6 actions were investigated in rat hepatocytes and H35 hepatoma cells. [Results]: C2-ceramide (N-acetylsphingosine) at 1-10 μM decreased MAT I/III expression. The effect was maximum after 2 h of treatment and it was maintained up to 24 h. MAT I/III protein levels also decreased. IL-6 (1-10 ng/ml) potentiated C2-ceramide effects in cultured hepatocytes while decreasing by itself MAT I/III levels with a similar time-response curve in both cell types. C2-ceramide actions were not associated with an increase in cell death. TNF-α was also a potent antagonist for MAT I/III expression, at 1-20 ng/ml decreased MAT I/III levels and induced endogenous ceramide generation. The decrease of MAT I/III mRNA levels (in all the cases) was not due to a decrease in mRNA half-life which suggests a regulation at the transcriptional level. Finally, the decrease in MAT I/III mRNA levels correlated to a decrease in MAT activity. [Conclusion]: This work demonstrates that short-chain ceramide can be used as a novel exogenous agonist that can modulate hepatic methionine metabolism in association with cytokines. © 2001 European Association for the Study of the Liver.
Identifiersdoi: 10.1016/S0168-8278(00)00022-2
issn: 0168-8278
e-issn: 1600-0641
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