Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 189, Issue 7, Pages 1413-1422Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2019.04.004
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Funding
- American Heart Association [0615393U]
- UPMC Children's Hospital of Pittsburgh Research Advisory Committee
- Cleveland Foundation
- Menten Endowment of the University of Pittsburgh
- Juvenile Diabetes Research Foundation Ltd. [7601]
- American Diabetes Association [7.07]
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Obesity is a major risk factor for type 2 diabetes because of chronic hepatic inflammation and resultant insulin resistance. Hepatocyte growth factor (HGF) is responsible for resetting hepatic homeostasis after injury following activation by urokinase-type plasminogen activator (u-PA; encoded by the PLAU gene). Plasminogen activator inhibitor type-1 (PAI-1; encoded by the SERPINE1 gene), a u-PA inhibitor and antifibrinolytic agent, is often elevated in obesity and is linked to cardiovascular events. We hypothesized that, in addition to its role in preventing fibrinolysis, elevated PAI-1 inhibits HGF's activation by u-PA and the resultant anti-inflammatory and hepatoprotective properties. Wild-type and PAI-1 knockout (KO) mice on a high-fat diet both became significantly heavier than lean controls; however, the obese KO mice demonstrated improved glucose metabolism compared with wild-type mice. Obese KO mice also exhibited an increase in conversion of latent single-chain HGF to active two-chain HGF, coinciding with an increase in the phosphorylation of the HGF receptor (HGFR or MET, encoded by the METgene), as well as dampened inflammation. These results strongly suggest that, in addition to its other functions, PAI-mediated inhibition of HGF activation prohibits the resolution of inflammation in the context of obesity-induced type 2 diabetes.
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