PPARδ ligand L-165041 ameliorates Western diet-induced hepatic lipid accumulation and inflammation in LDLR−/− mice

doi:10.1016/j.ejphar.2009.09.002

European Journal of Pharmacology

Volume 622, Issues 1–3, 10 November 2009, Pages 45-51

https://doi.org/10.1016/j.ejphar.2009.09.002 Get rights and content

Abstract

Although peroxisome proliferator-activated receptor delta (PPARδ) has been implicated in energy metabolism and lipid oxidation process, detailed roles of PPARδ in lipid homeostasis under pathologic conditions still remain controversial. Thus, we investigated the effect of PPARδ ligand L-165041 on Western diet-induced fatty liver using low-density lipoprotein receptor-deficient (LDLR^−/−) mice. LDLR^−/− mice received either L-165041 (5 mg/kg/day) or vehicle (0.1 N NaOH) with Western diet for 16 weeks. According to our data, L-165041 drastically reduced lipid accumulation in the liver, decreasing total hepatic cholesterol and triglyceride content compared to the vehicle group. Gene expression analysis demonstrated that L-165041 lowered hepatic expression of PPARγ, apolipoprotein B, interleukin 1 beta (IL-1β), and interleukin-6. In contrast, L-165041 increased hepatic expressions of PPARδ, lipoprotein lipase (LPL), and ATP-binding cassette transporter G1 (ABCG1). Our data suggest that L-165041 might be effective in preventing Western diet-induced hepatic steatosis by regulating genes involved in lipid metabolism and the inflammatory response.

Introduction

Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors that regulate various metabolic processes by acting as transcription factors. The peroxisome proliferator-activated receptors family consists of three structurally similar isoforms, α, δ, and γ (Takano et al., 2004). Among these different isoforms, the least studied PPARδ is known to be widely expressed in many different types of tissue (Ahmed et al., 2007). Although synthetic PPARδ ligands have not been fully approved for clinical applications, studies to elucidate their pharmacological effects have been ongoing since they were first synthesized and results are now accumulating.

PPARδ has been reported to be involved in developmental regulation (Braissant and Wahli, 1998), energy homeostasis (Berger et al., 2005), and lipid metabolism (Leibowitz et al., 2000). In the hepatic system, a synthetic PPARδ ligand has been reported to induce hepatic lineage cell proliferation (Hellemans et al., 2003, Glinghammar et al., 2003). In addition, some beneficial effects of PPARδ on hepatic lipid metabolism, including an attenuation of hepatic fat accumulation in leptin-deficient (ob/ob) mice (Wang et al., 2003) and an improvement in hepatic inflammation and subsequent steatohepatitis (Nagasawa et al., 2006), have been reported. Nevertheless, a more defined role of PPARδ in hepatic lipid metabolism under pathologic conditions such as hepatic steatosis remains to be determined.

A high-fat diet can lead to the hepatic accumulation of dietary fat and cause inflammation (Lavoie and Gauthier, 2006). Moreover, a significant accumulation of fat in the liver is considered to be one of the common features of metabolic syndromes such as obesity, diabetes, and hyperlipidemia (Abdeen et al., 2006). In general, hepatic lipid accumulation can compromise hepatic function, and further develop into cirrhosis or hepatocellular carcinoma. Therefore, a need exists to clarify its regulatory mechanisms and develop a pharmaceutical agent to control its development and subsequent hepatic steatosis (Nagasawa et al., 2006).

In the present study, we evaluated the effect of a synthetic PPARδ ligand, L-165041 ([4-3-(4-Acetyl-3-dydroxyl-2-propylphenoxy propoxy) phenoxy] acetic acid), on the accumulation of hepatic lipids induced by a Western diet in low-density lipoprotein receptor-deficient (LDLR^−/−) mice. According to our data, L-165041 treatment significantly inhibited hepatic lipid accumulation, reducing the amount of total cholesterol and hepatic triglycerides. In addition, L-165041 diminished the gene expressions of PPARγ, apoB, and inflammatory cytokines induced by a Western diet. Our data suggest that L-165041 might be an effective agent for preventing hepatic lipid accumulation by modulating lipid metabolism and inflammation processes.

Section snippets

Animals and diet

The animals used for this study were 7–9-week-old female B6;129S-Ldlr^tm1Her mice (Orient Charles River Technology, Seoul, Korea) fed a Western diet (21% milk fat, 0.15% cholesterol, 19.5% casein, 0.3% dl-methionine, 15% cornstarch, 34.146% sucrose, 5% cellulose, 3.5% salt mix, 1% vitamin mix, 0.4% calcium carbonate, 0.0004% ethoxyquin). A synthetic PPARδ ligand, L-165041, was purchased from Tocris (Ellisville, MO). LDLR^−/− mice were divided into vehicle (0.1 N NaOH) and L-165041 (5 mg/kg/day)

Effects of L-165041 on the serum lipid profile of LDLR^−/− mice fed a Western diet

After 16 weeks on the Western diet, the serum levels of total cholesterol, triglycerides, and low-density lipoproteins were significantly elevated in both the vehicle and L-165041 group compared to baseline. However, no significant difference was observed between the vehicle and L-165041 groups in terms of serum lipid parameters. In addition, no differences in the liver weight were detected (Table 2).

Effect of L-165014 on hepatic lipid accumulation

To examine the effect of general morphology, we performed histological analysis after

Discussion

Ubiquitously expressed, PPARδ has been implicated in lipid metabolism and energy homeostasis of various tissue types including the liver. In lipid metabolism, PPARδ agonist has been reported to increase high-density lipoproteins in animal models (Graham et al., 2005) and regulate fatty acid oxidation in cardiomyocytes and skeletal muscles (Planavila et al., 2005). Although these previous studies demonstrated some beneficial effects of PPARδ on the lipid profile, much of the underlying mechanism

Acknowledgments

This work was supported by a Korea National Institute of Health intramural research grant (4800-4845-300-210, 2008-N00406-00).

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Pulmonary, Gastrointestinal and Urogenital PharmacologyPPARδ ligand L-165041 ameliorates Western diet-induced hepatic lipid accumulation and inflammation in LDLR−/− mice

Abstract

Introduction

Section snippets

Animals and diet

Effects of L-165041 on the serum lipid profile of LDLR−/− mice fed a Western diet

Effect of L-165014 on hepatic lipid accumulation

Discussion

Acknowledgments

Trends Pharmacol. Sci.

J. Lipid Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Atherosclerosis

Gastroenterology

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Eur. J. Pharmacol.

J. Lipid Res.

Am. J. Pathol.

J. Biol. Chem.

J. Lipid Res.

Cell

Biochem. Biophys. Res. Commun.

Pulmonary, Gastrointestinal and Urogenital Pharmacology
PPARδ ligand L-165041 ameliorates Western diet-induced hepatic lipid accumulation and inflammation in LDLR^−/− mice

Effects of L-165041 on the serum lipid profile of LDLR^−/− mice fed a Western diet