Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate.

Yusuke Sasaki,Kentaro Murakami,Sana Raza-Iqbal,Tsuyoshi Osawa,Tatsuhiko Kodama,Juro Sakai,Toshiya Tanaka,Yoshihiro Matsumura,Motonobu Anai

doi:10.3390/ijms20225682

Abstract

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

Highlights

Low density lipoprotein cholesterol (LDL-C)-lowering therapy by statins has been proven to reduce the events of atherosclerotic cardiovascular disease (ASCVD) [1,2], there still remains a high residual cardiovascular risk from elevated triglycerides (TG) and low HDL cholesterol (HDL-C) levels [3,4,5,6]
Besides its role in inflammation and reactive oxygen species (ROS) production, we found that pemafibrate suppresses high glucose-induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs)
Despite accumulating evidence of the residual cardiovascular risks resulting from elevated TGs and lower HDL-C levels, low potent synthetic PPARα agonists have not shown enough evidence to reduce the definitive mortality rate when combined with statin treatment, despite an improvement in dyslipidemia

Summary

Introduction

Low density lipoprotein cholesterol (LDL-C)-lowering therapy by statins has been proven to reduce the events of atherosclerotic cardiovascular disease (ASCVD) [1,2], there still remains a high residual cardiovascular risk from elevated triglycerides (TG) and low HDL cholesterol (HDL-C) levels [3,4,5,6]. The use of fibrates in patients with hepatic and renal insufficiency has been limited due to adverse drug reactions (ADRs) such as plasma transaminase and creatinine elevation, as well as reduced estimated glomerular filtration rates (eGFRs) [11,12,13,14]. Under these circumstances, pemafibrate was developed as a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that enhances the beneficial effects and reduces the adverse effects of fibrates. We describe the pemafibrate-regulated genes and potential clinical implications

Pemafibrate as a Novel SPPARMα

Pemafibrate Regulates the Availability of FA and Glucose Oxidation

Possible Mechanism for the Gene Expression Regulation Induced by Pemafibrate?

Conclusions