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An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1

Ze Zheng, Lalitha Nayak, Wei Wang, Arif Yurdagul Jr., Xiaobo Wang, Bishuang Cai, Stephanie Lapping, Lale Ozcan, Rajasekhar Ramakrishnan, Richard G. Pestell, Mukesh K. Jain and Ira Tabas

Key points

  • Hepatocyte-derived tPA contributes to basal circulating tPA activity and affects injury-induced fibrinolysis.

  • Hepatocyte tPA is induced by ATF6 and subjected to negative regulation by the co-repressor DACH1.

Abstract

Tissue-type plasminogen activator (tPA) is a major mediator of fibrinolysis and thereby prevents excessive coagulation without compromising hemostasis. Studies on tPA regulation have focused on its acute, local release by vascular cells in response to injury or other stimuli. However, very little is known about sources, regulation, and fibrinolytic function of non-injury-induced systemic plasma tPA. We explore here the role and regulation of hepatocyte-derived tPA as a source of basal plasma tPA activity and as a contributor to fibrinolysis after vascular injury. We show that hepatocyte tPA is down-regulated by a pathway in which the co-repressor DACH1 represses ATF6, which is an inducer of the tPA gene Plat. Hepatocyte-DACH1-knockout mice show increases in liver Plat, circulating tPA, fibrinolytic activity, bleeding time, and time-to-thrombosis, which are reversed by silencing hepatocyte Plat. Conversely, hepatocyte-ATF6-knockout mice show decreases in these parameters. The inverse correlation between DACH1 and ATF6/PLAT is conserved in human liver. These findings reveal a regulated pathway in hepatocytes that contributes to basal circulating levels of tPA and to fibrinolysis after vascular injury.

  • Submitted July 20, 2018.
  • Accepted November 13, 2018.