Journal Article

Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity

Schrope, Beth, Liu, Rui-Ming, Ozcan, Lale, Tabas, Ira, Krikhely, Abraham, López, José A., Wang, Xiaobo, Zheng, Ze, Gershbaum, Shana, Nakamura, Keiko, Thomas, Sherry, Bessler, Marc

2020

Overview

Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA-PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene corepressor Rev-Erbα increased PAI-1, which then increased the tPA gene PLAT via a PAI-1/LRP1/PKA/p-CREB1 pathway. This pathway was partially counterbalanced by increased DACH1, a PLAT-negative regulator. We focused on the PAI-1/PLAT pathway, which mitigates the reduction in fibrinolysis in obesity. Thus, silencing hepatocyte PAI-1, CREB1, or tPA in obese mice lowered plasma tPA and further impaired fibrinolysis. The PAI-1/PLAT pathway was present in primary human hepatocytes, and associations among PAI-1, tPA, and PLAT in livers from obese and lean humans were consistent with these findings. Knowledge of PAI-1 and tPA regulation in hepatocytes in obesity may suggest therapeutic strategies for improving fibrinolysis and lowering the risk of thrombosis in this setting.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Defects / Eye Proteins - genetics / Eye Proteins - metabolism / Fibrinolysis / Genes / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Humans / Liver / Metabolism / Mice / Mice, Knockout / Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics / Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism / Obesity / Obesity - genetics / Obesity - metabolism / Obesity - pathology / Plasma / Plasminogen Activator Inhibitor 1 - genetics / Plasminogen Activator Inhibitor 1 - metabolism / Plasminogen activator inhibitors / Protein kinase A / Proteins / Regulation / Serpin E2 - genetics / Serpin E2 - metabolism / Severity of Illness Index / Signal Transduction / t-Plasminogen activator / Thrombolytic drugs / Thrombosis / Tissue plasminogen activator / Tissue Plasminogen Activator - genetics / Tissue Plasminogen Activator - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism