Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice.

Yujin Shin,Dongju Lee,Soon Shik Shin,Michung Yoon,Mijeong Lee,Joonseong Jang

doi:10.3390/ijms22073675

Abstract

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (−38%, p < 0.05), visceral adipose tissue mass (−46%, p < 0.05), and visceral adipocyte size (−20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (−69%, p < 0.05) and infiltration of macrophages (−72%, p < 0.05), while concomitantly upregulating the expression of fatty acid β-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

Highlights

Fibrates act as nuclear peroxisome proliferator-activated receptor α (PPARα) ligands and modulate the expression of genes that are crucial for lipid and lipoprotein metabolism, thereby contributing to lipid homeostasis [1,2]
OVX mice that were fed an high-fat diet (HFD) supplemented with fenofibrate (HFD-FF mice; 16.80 ± 1.41 g) had lower body weight gains after 21 weeks of administration compared with HFD-fed mice (HFD mice; 27.10 ± 4.97 g) (Figure 1A)
Compared with low-fat diet (LFD)-fed mice (LFD mice), HFD mice had increased plasma concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and they were reduced by 76% and 29%, respectively, in HFD-FF mice compared with HFD mice (Figure 2A,B)

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Fibrates act as nuclear peroxisome proliferator-activated receptor α (PPARα) ligands and modulate the expression of genes that are crucial for lipid and lipoprotein metabolism, thereby contributing to lipid homeostasis [1,2]. Fibrate-activated PPARα forms heterodimers with the retinoid X receptor and binds to PPAR response elements in promoter regions of target genes, which have functions in the plasma triglyceride hydrolysis, fatty acid uptake and binding, and fatty acid β–oxidation [3,4,5]. The activation of PPARα target genes promotes the oxidation of fatty acids, increases the breakdown of triglycerides, and reduces triglyceride synthesis and secretion

Methods

Results

Conclusion