Dn. Brindley et al., CROSS-TALK BETWEEN THE BIOACTIVE GLYCEROLIPIDS AND SPHINGOLIPIDS IN SIGNAL-TRANSDUCTION, Biochemistry and cell biology, 74(4), 1996, pp. 469-476
Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of
phospholipase D produces phosphatidate that can be converted to lysop
hosphatidate and diacylglycerol. Diacylglycerol is an activator of pro
tein kinase C, whereas phosphatidate and lysophosphatidate stimulate t
yrosine kinases and activate the Ras-Raf-mitogen-activated protein kin
ase pathway. These three lipids can stimulate cell division. Conversel
y, activation of sphingomyelinase by agonists (e.g., tumor necrosis fa
ctor-alpha) causes ceramide production that inhibits cell division and
produces apoptosis. If ceramides are metabolized to sphingosine and s
phingosine 1-phosphate, then these lipids can stimulate phospholipase
D and are also mitogenic. By contrast, ceramides inhibit the activatio
n of phospholipase D by decreasing its interaction with the G-proteins
, ARF and Rho, which are necessary for its activation. In whole cells,
ceramides also stimulate the degradation of phosphatidate, lysophosph
atidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a m
ultifunctional phosphohydrolase (the Mg2+-independent phosphatidate ph
osphohydrolase), whereas sphingosine inhibits phosphatidate phosphohyd
rolase. Tumor necrosis factor-alpha causes insulin resistance, which m
ay be partly explained by ceramide production. Cell-permeable ceramide
s decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes afte
r 2-24 h, whereas they stimulate basal glucose uptake. These effects d
o not depend on decreased tyrosine phosphorylation of the insulin rece
ptor and insulin receptor substrate-1 or the interaction of insulin re
ceptor substrate-1 with phosphatidylinositol 3-kinase. They appear to
rely on the differential effects of ceramides on the translocation of
GLUT1- and GLUT4-containing vesicles. It is concluded that there is a
significant interaction and ''cross-talk'' between the sphingolipid an
d glycerolipid pathways that modifies signal transduction to control v
esicle movement, cell division, and cell death.