Biochemical and Biophysical Research Communications
Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process
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.
Section snippets
Animal treatment
Eight week-old mice C57BL/6 mice were purchased from Orient Bio (Seongnam, Korea). Maintenance of mice and the experimental protocol were followed according to a standard animal protocol approved by the Animal Care and Use Committee at Wonkwang University. Mice were maintained for a week on a standard commercial diet (Research Diet Inc. USA) and then divided into four groups: fed (n = 6), fed+feno (n = 6), refed (n = 6) and refed+feno (n = 6). Both fed+feno and refed+feno groups of mice were received
Fenofibrate protects against liver damage caused by fasting–refeeding HFD
Fasting and refeeding diets are known to be associated with alterations in hepatic lipid and glucose metabolism which dramatically enhances expression of lipid metabolizing genes [19], [20]. Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is known to possess lipid-lowering effects and to decrease serum TG level in non-alcoholic fatty liver disease (NAFLD) [21], [22], [23]. Therefore, to determine the effects of fasting–refeeding high fat diet (HFD) and fenofibrate
Discussion
In the current study, we used fenofibrate, a PPARα agonist, to examine the effect of PPARα activity on hepatic lipid metabolism in response to a fasting–refeeding HFD process that mimics a bad eating habit. By analyzing the liver tissues from mice subject to the fasting–refeeding process, we found that the fasting–refeeding HFD induces ballooning degradation of liver cells, hepatic triglyceride accumulation, and activation of NF-κB and its target genes. Therefore, a fasting–refeeding HFD
Disclosure
All the authors declared no competing interests.
Acknowledgment
This work was supported by the two National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP): (No. 2011-0028866) and (No. 2011-0030718).
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Dietary fenofibrate attenuated high-fat-diet-induced lipid accumulation and inflammation response partly through regulation of pparα and sirt1 in juvenile black seabream (Acanthopagrus schlegelii)
2020, Developmental and Comparative ImmunologyCitation Excerpt :Similar results have been reported in fish species, showing that dietary fenofibrate supplementation could modulate lipid deposition by up-regulating the expression of lipid metabolism genes, such as cpt1a in yellow catfish (Pelteobagrus fulvidraco) (Zheng et al., 2015) and Nile tilapia (Oreochromis niloticus) (Ning et al., 2019). Furthermore, Pparα not only affects genes of lipid metabolism, but also impacts inflammatory signaling pathways by directly interacting with nuclear factor kB (NF-κB) to influence mRNA expression levels of inflammatory genes such as interleukin 6 (il-6) receptor (Desvergne and Wahli, 1999; Lee et al., 2013; Stienstra et al., 2007). Moreover, studies in mammals indicated that PPARα works in combination with silent information regulator 1 (sirt1) to relieve inflammation and metabolic dysregulation to protect heart (Oka et al., 2012; Planavila et al., 2010).
Peroxisomal Fitness: A Potential Protective Mechanism of Fenofibrate against High Fat Diet-Induced NonAlcoholic Fatty Liver Disease in Mice
2022, Diabetes and Metabolism JournalHepatic transcriptional responses to fasting and feeding
2021, Genes and Development
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These authors contributed equally to this work.