Abstract
Background:Obesity is associated with a prothrombotic state, which may contribute to the increased risk of thrombotic events.Objective:To assess the effects of (pre)adipocyte-derived adipokines on fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) production by hepatocytes.Methods:HepG2 hepatocytes were incubated with conditioned media (CM) derived from preadipocytes and adipocytes, which had been untreated or prestimulated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β or IL-6. After 24 h, supernatants and cell lysates were harvested for measurement of fibrinogen, PAI-1 and TF.Results:(Pre)adipocyte CM significantly enhanced the production of PAI-1 by HepG2 cells 2.5- to 4.4-fold. CM from cytokine-stimulated (pre)adipocytes significantly induced fibrinogen secretion 1.5- to 4.2-fold. TF production was not affected by the CM. After specific depletion of TNF-α, IL-1β or IL-6 from the CM, IL-6 was shown to be the most prominent stimulus of fibrinogen secretion and IL-1β of PAI-1 secretion. In addition, fibrinogen, PAI-1 and tissue factor production was evaluated by direct stimulation of HepG2 cells with TNF-α, IL-1β or IL-6. IL-6 enhanced fibrinogen synthesis 4.3-fold (P<0.01), whereas IL-1β induced PAI-1 production 5.0-fold (P<0.01). Gene expression analyses showed that TNF-α and IL-1β stimulate the adipocyte expression of TNF-α, IL-1β and IL-6. Cytokine stimulation of adipocytes may thus have induced an inflammatory response, which may have stimulated fibrinogen and PAI-1 production by HepG2 cells more potently.Conclusions:SGBS (pre)adipocytes release cytokines that increase the production of fibrinogen and PAI-1 by HepG2 cells. IL-6 and IL-1β produced by (pre)adipocytes were the strongest inducers of fibrinogen and PAI-1 secretion, respectively.
Highlights
Abdominal obesity is strongly related to insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and vascular complications.[1,2,3] In addition to metabolic derangements, resulting in insulin resistance and low-grade inflammation, obesity is characterized by abnormalities in hemostasis, coagulation and fibrinolysis, contributing to arterial and venous thrombosis.[4]
As a model for investigating the potential of adipose tissue to influence the production of procoagulant factors by the liver, this study evaluated the effects of conditioned media (CM) from preadipocytes and & 2012 Macmillan Publishers Limited
The current results demonstrate that IL-6 inadipocyte CM stimulates the production of fibrinogen by HepG2 cells and that IL-1b and tumor necrosis factor (TNF)-a inadipocyte CM induce an increase in plasminogen activator inhibitor-1 (PAI-1) production by HepG2 cells (Figure 5)
Summary
Abdominal obesity is strongly related to insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and vascular complications.[1,2,3] In addition to metabolic derangements, resulting in insulin resistance and low-grade inflammation, obesity is characterized by abnormalities in hemostasis, coagulation and fibrinolysis, contributing to arterial and venous thrombosis.[4]. OBJECTIVE: To assess the effects of (pre)adipocyte-derived adipokines on fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) production by hepatocytes. RESULTS: (Pre)adipocyte CM significantly enhanced the production of PAI-1 by HepG2 cells 2.5- to 4.4-fold. CM from cytokinestimulated (pre)adipocytes significantly induced fibrinogen secretion 1.5- to 4.2-fold. Fibrinogen, PAI-1 and tissue factor production was evaluated by direct stimulation of HepG2 cells with TNF-a, IL-1b or IL-6. Cytokine stimulation of adipocytes may have induced an inflammatory response, which may have stimulated fibrinogen and PAI-1 production by HepG2 cells more potently. CONCLUSIONS: SGBS (pre)adipocytes release cytokines that increase the production of fibrinogen and PAI-1 by HepG2 cells. IL-6 and IL-1b produced by (pre)adipocytes were the strongest inducers of fibrinogen and PAI-1 secretion, respectively
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