Dr Ze Zheng
Associate Research Scientist, Columbia University Medical Center
Fibrinolysis is initiated by tissue plasminogen activator (tPA) and inhibited by its serpin inhibitor PAI1. The balance of tPA and PAI1 is critical for preventing excessive clotting without compromising hemostasis. Despite an increase in plasma tPA protein, obesity lowers blood tPA activity and fibrinolysis, but the mechanism is unknown. We have shown in lean mice that hepatocytes contribute substantially to basal plasma tPA and fibrinolysis and that hepatocyte tPA expression is repressed by DACH1 (Zheng Z. et al, Blood, 2019). Moreover, liver DACH1 correlates with body mass index in humans and body weight in mice, suggesting a possible mechanism that limits tPA in obesity.
We found that both tPA and PAI1 mRNAs were increased in the livers of obese mice vs. lean mice, the fold increase in PAI1 mRNA was greater than that of tPA. The net liver and plasma tPA activities were lower in obese mice. Similarly, palmitate increased both tPA and PAI1 mRNA in human primary hepatocytes, but net tPA activity in the medium was decreased. As expected, silencing PAI1 in these cells increased medium tPA activity. However, within hepatocytes, we uncovered a new PAI1 tPA “compensatory” pathway: si-PAI1 lowered tPA mRNA, and, conversely, PAI1 treatment of hepatocytes induced tPA mRNA. Next, silencing DACH1 in human primary hepatocytes markedly increased tPA mRNA, and silencing hepatocyte DACH1 in obese mice increased plasma tPA and fibrinolytic activity. In humans, tPA activity in plasma and liver was negatively correlated with liver DACH1, consistent with liver DACH1 as a negative regulator of tPA.
Dr. Ze Zheng is an Associate Research Scientist at Columbia University Medical Center in New York. She received her PhD in molecular biology and genetics of liver metabolism from Wayne State University in 2015. She has published 26 articles in leading journals on a broad range of topics, including liver metabolism, circadian rhythm, air pollution, cardiometabolic diseases such as hyperlipidemia, atherosclerosis, and thrombosis. Currently, Dr. Zheng studies the role of reduced hepatocyte-derived fibrinolytic activity in obesity-associated atherosclerosis and thrombosis. Her research is funded by a Berrie Scholar Award from Russell Berrie Foundation, an NIH T32 training grant, an ASH Scholar Award from American Society of Hematology, and a Career Development Award from American Heart Association. She serves as a member of the American Society of Hematology Trainee Council and Task Force for PhD Careers, and the International Society of Thrombosis and Haemostasis Ethics Committee.
Read more about Dr Ze Zheng here.
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