Role of PAI-1 in hepatic steatosis and dyslipidemia

Joshua A. Levine, Carlota Oleaga, Mesut Eren, Ansel P. Amaral, Meng Shang, Elizabeth Lux, Sadiya S. Khan, Sanjiv J. Shah, Yasuhiro Omura, Nathalie Pamir, Joshua Hay, Grant Barish, Toshio Miyata, Hagai Tavori, Sergio Fazio, Douglas E. Vaughan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number430
JournalScientific reports
Volume11
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • General

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