Background: In NASH the intracellular ratio of phosphatidylcholine (PC): lysophosphatidylcholine
(LPC) is decreased due to activation of phospholipase A2. Responsible is the calcium
independent membrane phospholipase A2 (iPLA2β) which is part of the heterotetrameric
fatty acid uptake complex consisting also of FABPPM, CD36 and caveolin1. The bile
acid-phospholipid conjugate UDCA-LPE inhibits fatty acid influx by interference with
iPLA2β.
Aim: Evaluation of the metabolic consequences of iPLA2β inhibition by UDCA-LPE in HepG2
cells.
Methods: In HepG2 cells the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide
(UDCA-LPE) as iPLA2β inhibitor was used to modify intracellular LPC levels. We examined
the impact of LPC on p-JNK1 and transcription of the heterotetrameric fatty acid transport
complex constituted of CD36, FABPPM, caveolin1 and iPLA2β.
Results: Inhibition of iPLA2β by UDCA-LPE resulted in suppression of cytosolic lysophosphatidylcholine
(LPC) which was accompanied by a corresponding decrease of phosphorylated JNK1. Low
pJNK1 suppressed the synthesis of all four members of the fatty acid uptake complex.
Thus, the complex faded from the detergent resistant plasma membrane fraction explaining
the inhibition of fatty acid influx in hepatocytes. The role of LPC as inducer of
pJNK1 was supported by in vitro addition of 1 – 10µM LPC to delipidated cytosolic
extracts. It resulted in pJNK1 dependent synthesis stimulation of the fatty acid uptake
complex.
Conclusion: The generation of LPC controls via JNK1 the constitution of the membrane fatty acid
uptake complex.
Corresponding author: Stremmel, Wolfgang
E-Mail:
wolfgang.stremmel@med.uni-heidelberg.de
