Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

Highlights

• A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit.

• A fasting–refeeding HFD induces liver ballooning injury.

• A fasting–refeeding HDF process elicits hepatic triglyceride accumulation.

• Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD.

Abstract

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

Introduction

Metabolic disorders, such as obesity, insulin resistance, and non-alcoholic fatty live disease caused by consuming a high-calorie diet, affect healthy life in developed countries [1]. Overnutrition potentially disturbs the nutrient homeostasis in human body and elicits chronic metabolic disorders [2]. Irregular eating habit, such as skipping meals or prolonged fasting, can also be a risk factor for metabolic syndrome [3], [4], [5]. Particularly, liver which is the major organ for controlling nutrient and energy homeostasis is affected by food availability [6], [7]. During prolonged fasting, free fatty acids released from adipose tissue are mobilized into liver and induce an abrupt change in the expression of genes involved in hepatic lipid and glucose metabolism [8]. Refeeding a high-carbohydrate and fat-free diet after fasting stimulates lipogenic gene expression and reactive oxygen species (ROS) production in hepatocytes [9]. Inconsistent food availabilities, such as overnutrition or meal irregularity, are associated with metabolic syndrome but the underlying molecular mechanism is largely unknown.

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear hormone receptor that controls lipid metabolism [10], [11]. PPARα is highly expressed in various tissues with high fatty acid oxidation rate, particularly in liver which regulates fatty acid catabolism [12]. In physiological condition, fasting stimulates PPARα activity to enhance the expression of genes involved in fatty acid uptake, mitochondrial fatty acid oxidation, peroxisomal fatty acid oxidation, peroxisome proliferation, and ketogenesis [13], [14], [15]. There are several endogenous ligands for PPARα activation such as fatty acids and fatty acid metabolites, whereas fibrates, including fenofibrate and clofibrate, are well known pharmacological PPARα agonists that are widely used in the treatment of dyslipidemia [16], [17]. In addition to its effects on lipid metabolism, PPARα also affects inflammatory signaling pathway by directly interacting with nuclear factor kB (NF-kB) to block inflammatory gene expression [18].

In the present study, we aimed to analyze the effects of fenofibrate treatment on a fasting–refeeding model which mimics irregular eating habit in hepatic lipid metabolism. Therefore, mice were fasted for 24 h, and then refed high fat diet for 16 h with or without twice injections of fenofibrate. Analysis on the liver tissues from mice subject to the fasting–refeeding process showed ballooning injury, neutral lipid accumulation, and NF-κB activation, implicating increased lipid mobilization to liver from nutrient. In contrast, fenofibrate treatment ameliorated the refeeding-mediated liver damage and reduced intrahepatic fat storage by inducing expression of genes closely related to fatty acid oxidation. Taken together, these findings indicate that a fasting–refeeding process impairs liver function potentially by accumulating triglycerides (TG) in hepatocytes, whereas activation of PPARα by fenofibrate treatment prevents the intrahepatic lipid storage by increasing fatty acid oxidation.