<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>We have shown that both free fatty acids (FFA)
and triglycerides (TG) increase expression of
plasminogen activator inhibitor type 1 (PAI-1)
in vivo and in vitro. To determine signaling
mechanisms responsible, HepG2 cells were
exposed to FFA, emulsified TG, or the combination.
The combination of FFA and TG
increased PAI-1 to a greater extent than either
agent alone (fold induction: 0.45mM FFA
1.7±0.2, 1000mg/dl TG 1.9±0.1, both 2.3±0.2,
n=10, p&lt;0.05 for comparison of combination
with either alone). Cells transfected with PAI-1
5' flanking region containing the 4G or 5G
polymorphism displayed similar activity in
response to FFA, but modestly greater activity
with the 4G polymorphism in response to TG
(fold induction: 5G-1.28±0.14 and 4G-
1.46±0.13, n=6, p&lt;0.05 for comparison).
Deletion analyses demonstrated that FFA and
TG induce PAI-1 expression through distinct
regions of the promoter. Inhibition of protein
kinase C inhibited the response to FFA but not
TG. Accordingly, increased FFA and TG contribute
to increased PAI- I through independent
mechanisms.</p>
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Int J Exp Diabetes Res. 2002; 3(2):109-118