The generation of the pro-inflammatory cytokines IL-6 and TNF-α by macrophages recruited to adipose tissue facilitates obesity-induced inflammation resulting in insulin resistance and type 2 diabetes (T2D). Increased adipose tissue is associated with inflammation and expression of acute phase response (APR) proteins secreted by the liver. Proper homeostasis of the liver is regulated by IL-6-depdendent expression of Hepatocyte Growth Factor (HGF) upon cleavage to its active form (aHGF) by the urokinase-type plasminogen activator (uPA). Plasminogen Activator Inhibitor Type-1 (PAI-1) is a pro-thrombotic APR protein known to inhibit the function of uPA; however, since HGFs activation, interaction and signaling through its receptor, MET are dependent upon uPA, PAI-1 is also capable of regulating the function of hepatic HGF. In vitro data demonstrates that aHGF significantly suppressed IL-6 production by macrophages stimulated with LPS via an increase in phosphorylation of GSK3β, rendering it inactive. Phosphorylated GSK3β correlated with increased retention of the phosphorylated NF-κB p65 subunit in the cytoplasm and an enhanced interaction between CBP and phosphorylated CREB resulting in IL-10 cytokine production. These changes were a direct result of signaling through MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice.
It is known that obese T2D patients present with an accumulation of PAI-1, which we hypothesize, results in the inactivation of HGF. The loss of HGF-MET signaling results in increased active GSK3β and the progression to unchecked inflammation and disease progression. In vivo studies using male, C57BL6 mice on a high fat diet alongside control fed mice demonstrates move severe hepatic steatosis in obese mice at 44 weeks compared to control. Steatosis coincided with the decrease in aHGF and elevated levels of PAI-1 protein. These results demonstrate that elevated levels of PAI-1 inhibit aHGF, leading to unresolved chronic inflammation in obesity and T2D.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11092010-140358 |
| Date | 11 November 2010 |
| Creators | Coudriet, Gina Marie |
| Contributors | Youhua Liu, Ph.D., Robert M. O'Doherty, Ph.D., Nick Giannoukakis, Ph.D., Wendy M. Mars, Ph.D., Jon D. Piganelli, Ph.D., H. Henry Dong, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11092010-140358/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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