Role of PAI-1 in hepatic steatosis and dyslipidemia.

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

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.

FATTY degeneration; DYSLIPIDEMIA; PLASMINOGEN activator inhibitors; METABOLIC syndrome; BIOMARKERS

Scientific Reports, 2021, Vol 11, Issue 1, p1

2045-2322

Academic Journal

10.1038/s41598-020-79948-x