Faculty Collaboration Database

An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood 2019 Feb 14;133(7):743-753

Date

12/07/2018

Pubmed ID

30504459

Pubmed Central ID

PMC6376283

DOI

10.1182/blood-2018-07-864843

Scopus ID

2-s2.0-85061475922 (requires institutional sign-in at Scopus site)   23 Citations

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 noninjury-induced systemic plasma tPA. We explore 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 downregulated by a pathway in which the corepressor 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.

Author List

Zheng Z, Nayak L, Wang W, Yurdagul A Jr, Wang X, Cai B, Lapping S, Ozcan L, Ramakrishnan R, Pestell RG, Jain MK, Tabas I

Author

Ze Zheng PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Activating Transcription Factor 6
Animals
Cells, Cultured
Eye Proteins
Female
Fibrinolysis
Fibrinolytic Agents
Hepatocytes
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Thrombosis
Tissue Plasminogen Activator
Transcription Factors