PMID- 11281546
OWN - NLM
STAT- MEDLINE
DCOM- 20010726
LR  - 20190817
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 34
IP  - 2
DP  - 2001 Feb
TI  - Short-chain ceramide regulates hepatic methionine adenosyltransferase expression.
PG  - 192-201
AB  - 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-alpha 
      (TNF-alpha) and interleukin-6 (IL-6) are two cytokines fundamental for liver 
      regeneration. TNF-alpha 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-alpha and IL-6 actions were investigated in rat hepatocytes and H35 
      hepatoma cells. RESULTS: C2-ceramide (N-acetylsphingosine) at 1-10 microM 
      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-alpha 
      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.
FAU - Frago, L M
AU  - Frago LM
AD  - Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de 
      Investigaciones Cientificas-Universidad Autonoma de Madrid, Spain.
FAU - Paneda, C
AU  - Paneda C
FAU - Fabregat, I
AU  - Fabregat I
FAU - Varela-Nieto, I
AU  - Varela-Nieto I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Interleukin-6)
RN  - 0 (Isoenzymes)
RN  - 0 (N-acetylsphingosine)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.5.1.6 (Methionine Adenosyltransferase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Hepatocytes/drug effects/metabolism
MH  - Interleukin-6/pharmacology
MH  - Isoenzymes/genetics/metabolism
MH  - Liver/*drug effects/*metabolism
MH  - Liver Neoplasms, Experimental/genetics/metabolism
MH  - Liver Regeneration/drug effects/physiology
MH  - Methionine/metabolism
MH  - Methionine Adenosyltransferase/*genetics/*metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Sphingosine/analogs & derivatives/*pharmacology
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2001/04/03 10:00
MHDA- 2001/07/28 10:01
CRDT- 2001/04/03 10:00
PHST- 2001/04/03 10:00 [pubmed]
PHST- 2001/07/28 10:01 [medline]
PHST- 2001/04/03 10:00 [entrez]
AID - S0168827800000222 [pii]
AID - 10.1016/s0168-8278(00)00022-2 [doi]
PST - ppublish
SO  - J Hepatol. 2001 Feb;34(2):192-201. doi: 10.1016/s0168-8278(00)00022-2.