1. Role of PAI-1 in hepatic steatosis and dyslipidemia
- Author
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Yasuhiro Omura, Joshua A. Levine, Joshua Hay, Carlota Oleaga, Toshio Miyata, Nathalie Pamir, Grant D. Barish, Sanjiv J. Shah, Douglas E. Vaughan, Hagai Tavori, Sergio Fazio, Mesut Eren, Elizabeth Lux, Sadiya S. Khan, Ansel Philip Amaral, and Meng Shang
- Subjects
Male ,medicine.medical_specialty ,FGF21 ,Science ,Mice, Transgenic ,Article ,Cohort Studies ,chemistry.chemical_compound ,Mice ,Insulin resistance ,Internal medicine ,Plasminogen Activator Inhibitor 1 ,medicine ,Animals ,Humans ,Dyslipidaemias ,Cells, Cultured ,Dyslipidemias ,Multidisciplinary ,business.industry ,Lipid metabolism ,Hep G2 Cells ,medicine.disease ,Lipid Metabolism ,Metabolic syndrome ,Biomarker (cell) ,Fatty Liver ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Plasminogen activator inhibitor-1 ,Medicine ,Female ,Steatosis ,Proprotein Convertase 9 ,business ,Dyslipidemia ,Non-alcoholic fatty liver disease - Abstract
Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.
- Published
- 2021