Function and metabolism
Substitution of marine lipids
in cell signallings
Alain Legrand
Université de Rennes 1, faculté des sciences pharmaceutiques et biologiques,
laboratoire de pharmacodynamie et pharmacologie moléculaire, 2 av. Pr Léon Bernard,
35043 Rennes Cedex, France - alain.legrand@univ-rennesl.fr
Receptor-coupled activation of phospholipases initiates the cleavage of
membrane phospholipids (PL) and the formation of many lipidic mediators
and second messengers with proeminent roles in cell functions and
communications. These newly-produced bioactives lipids include second
messengers such as diacylglycerol (DAG), inositol-1,4,5 triphosphate (IP3),
phosphatidic acid (PA), and ceramide, and mediators such as eicosanoids, platelet activating factor (PAF), lyso-PA, anandamide and 2-arachidonoylglycerol. In most tissues lipidic structure of the membrane
possess an important plasticity depending of the availability of fatty
acids and other membrane PL precursors. This variability may in turn
affect the structure and thus the functions of lipidic mediators and
messengers which are not produced as single compounds, but rather
represent families depending on their precursors.
Marme organisms are rich in specific lipids such as the (n-3) unsaturated fatty acid eicosapentaenoic acid (EPA), or 1-O-alkylglycerols (AKGs)
abundant in shark liver oil.
These lipids may be incorporated into the PL of cultured cells.
We have demonstrated that the human transformed monocyte-like
cells THP-1 cells incorporated either EPA or arachidonic acid (AA) on
the position 2 of the glycerol of 1-acyl- and 1-alkylphosphatidylcholine (PC). Under stimulation, these cells produce PAF by phospholipase
A2 (PLA2) hydrolysis of 1-alkyl-PC followed by acetylation of glycerol
at the 2 position. Since PLA2 has some selectivity for AA, substitution
by AA or EPA resulted in a significant difference in PAF production. PAF
production under calcium ionophore A23187 stimulation (1 µM, 20min)
was increased by 130.7% and 48%, after AA or EPA supplementation
(25 µM, 7days), respectively. THP-1 cells incorporated also AKG proeminently into 1-alkyl-PC, and this resulted in an increased production
of PAF under A23187 stimulation. In cultured endothelial cells, AKG
are incorporated prominently as well into 1-alkyl-PC. Under cell receptor stimulation, PC is hydrolyzed by activated phospholipase C and/or
D (PLC/PLD), resulting in the production of DAG, a second messenger involved in protein kinase C activation. We hypothezied that 1-alkyl-PC,
could be used as a substrat by these activated PLC/PLD, producing
1-alkyl-2-acylglycerol (AKAG), an analog of DAG with inhibitory activity
on certain PKC subtypes. We demonstrated that AKG incorporation,
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Substitution of marine lipids
in cell signallings
Alain Legrand
Université de Rennes 1, faculté des sciences pharmaceutiques et biologiques,
laboratoire de pharmacodynamie et pharmacologie moléculaire, 2 av. Pr Léon Bernard,
35043 Rennes Cedex, France - alain.legrand@univ-rennesl.fr
Receptor-coupled activation of phospholipases initiates the cleavage of
membrane phospholipids (PL) and the formation of many lipidic mediators
and second messengers with proeminent roles in cell functions and
communications. These newly-produced bioactives lipids include second
messengers such as diacylglycerol (DAG), inositol-1,4,5 triphosphate (IP3),
phosphatidic acid (PA), and ceramide, and mediators such as eicosanoids, platelet activating factor (PAF), lyso-PA, anandamide and 2-arachidonoylglycerol. In most tissues lipidic structure of the membrane
possess an important plasticity depending of the availability of fatty
acids and other membrane PL precursors. This variability may in turn
affect the structure and thus the functions of lipidic mediators and
messengers which are not produced as single compounds, but rather
represent families depending on their precursors.
Marme organisms are rich in specific lipids such as the (n-3) unsaturated fatty acid eicosapentaenoic acid (EPA), or 1-O-alkylglycerols (AKGs)
abundant in shark liver oil.
These lipids may be incorporated into the PL of cultured cells.
We have demonstrated that the human transformed monocyte-like
cells THP-1 cells incorporated either EPA or arachidonic acid (AA) on
the position 2 of the glycerol of 1-acyl- and 1-alkylphosphatidylcholine (PC). Under stimulation, these cells produce PAF by phospholipase
A2 (PLA2) hydrolysis of 1-alkyl-PC followed by acetylation of glycerol
at the 2 position. Since PLA2 has some selectivity for AA, substitution
by AA or EPA resulted in a significant difference in PAF production. PAF
production under calcium ionophore A23187 stimulation (1 µM, 20min)
was increased by 130.7% and 48%, after AA or EPA supplementation
(25 µM, 7days), respectively. THP-1 cells incorporated also AKG proeminently into 1-alkyl-PC, and this resulted in an increased production
of PAF under A23187 stimulation. In cultured endothelial cells, AKG
are incorporated prominently as well into 1-alkyl-PC. Under cell receptor stimulation, PC is hydrolyzed by activated phospholipase C and/or
D (PLC/PLD), resulting in the production of DAG, a second messenger involved in protein kinase C activation. We hypothezied that 1-alkyl-PC,
could be used as a substrat by these activated PLC/PLD, producing
1-alkyl-2-acylglycerol (AKAG), an analog of DAG with inhibitory activity
on certain PKC subtypes. We demonstrated that AKG incorporation,
189