ArticleThe Journal of clinical investigation2020
Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 47 citations in OpenAlex.
- Assays to quantify fibrinolysis: strengths and limitations. Communication from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on fibrinolysis.Journal of thrombosis and haemostasis : JTH · 2023Guideline
- Selected biomarkers of coagulation, inflammation, and vascular tone in young women with normal weight obesity.International journal of obesity (2005) · 2026Article
- Apolipoprotein B100 and white matter hyperintensity as distinct mediators of thrombolytic response in acute stroke: preliminary findings.Journal of thrombosis and thrombolysis · 2026Article
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- The Obesity Paradox in Major Adverse Cardiovascular Events After PCI for Acute Coronary Syndrome: A Narrative Review.Journal of cardiovascular development and disease · 2026Review
- Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver.bioRxiv : the preprint server for biology · 2026Article
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- The Double-Edged Sword Effect of the Fibrinolytic System in Alzheimer's Disease.Cellular and molecular neurobiology · 2026Review
- PAI-1 is a common driver of aging and diverse diseases.Biomedical journal · 2026Review
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- Association between lipid profiles and early clinical outcomes in acute ischemic stroke: a single-center cohort study in the Chinese population.BMC neurology · 2025Article
- Plasminogen activation and plasmin activity are not necessary to prevent venous thrombosis/thromboembolism.Blood · 2025Observational
- Endothelial GATA3 is involved in coagulofibrinolytic homeostasis during endotoxin sepsis.Experimental animals · 2025Article
- The role of macrophages in vascular calcification: strategies for diagnosis and treatment.Frontiers in immunology · 2025Review
- Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease.Cellular and molecular gastroenterology and hepatology · 2025Review
- Visceral Adipose Tissue Inflammation and Vascular Complications in a Rat Model with Severe Dyslipidemia: Sex Differences and PAI-1 Tissue Involvement.Biomolecules · 2024Article
- RNA-Seq-Based Transcriptome Analysis of Chinese Cordyceps Aqueous Extracts Protective Effect against Adriamycin-Induced mpc5 Cell Injury.International journal of molecular sciences · 2024Article
- Liver-specific glucocorticoid action in alcoholic liver disease: Study of glucocorticoid receptor knockout and knockin mice.Liver research (Beijing, China) · 2024Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.