Role of PAI-1 in hepatic steatosis and dyslipidemia

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

doi:10.1038/s41598-020-79948-x

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.

Highlights

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome
To investigate the mechanistic role of PAI-1 in hepatic lipid metabolism, RNA sequencing (RNA-seq) was performed on hepatic mRNA from mice treated with TM5614, a novel orally active small molecule inhibitor of PAI-1, and compared their gene expression patterns with those from hepatic mRNA collected from age-matched littermate control mice consuming a standard chow (SC) diet
Hierarchical clustering and gene ontology analysis revealed that short-term administration of a PAI-1 inhibitor generated a coordinated, robust, and significant alteration in the expression of numerous genes involved in metabolism of lipids (160 genes) and fatty acid metabolism (156 genes) in response to treatment (Fig. 1C, S1A)

Summary

Introduction

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. To exclude the influence of an off-target effect of the drug on the observed alterations in hepatic gene expression, a similar set of studies was performed using heterozygous PAI-1 deficient mice (Pai-1+/−) and wild-type (WT) littermate controls. Cluster analysis indicated homogeneity amongst samples in each group, with multiple changes in RNA expression across the genome induced by lower PAI-1 levels (Fig. 2A).

Results

Conclusion