A Noncanonical Role for Plasminogen Activator Inhibitor Type 1 in Obesity-Induced Diabetes.

Autor:	Coudriet GM; Department of Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Stoops J; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Orr AV; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Bhushan B; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Koral K; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Lee S; Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Previte DM; Department of Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Dong HH; Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Michalopoulos GK; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Mars WM; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: wmars@pitt.edu., Piganelli JD; Department of Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: jdp51@pitt.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2019 Jul; Vol. 189 (7), pp. 1413-1422. Date of Electronic Publication: 2019 May 02.
DOI:	10.1016/j.ajpath.2019.04.004
Abstrakt:	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 MET gene), 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. (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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