Linalool is a PPARα ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome

Hee-Jin Jun,Ji Hae Lee,Jiyoung Kim,Yaoyao Jia,Kyoung Heon Kim,Kwang Yeon Hwang,Eun Ju Yun,Kyoung-Rok Do,Sung-Joon Lee

doi:10.1194/jlr.m045807

Abstract

We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time-resolved fluorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPARα. Linalool stimulation reduced cellular lipid accumulation regulating PPARα-responsive genes and significantly induced FA oxidation, and its effects were markedly attenuated by silencing PPARα expression. In mice, the oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-diet-fed C57BL/6J mice (31%, P < 0.05) and human apo E2 mice (50%, P < 0.05) and regulated hepatic PPARα target genes. However, no such effects were seen in PPARα-deficient mice. Transcriptome profiling revealed that linalool stimulation rewired global gene expression in lipid-loaded hepatocytes and that the effects of 1 mM linalool were comparable to those of 0.1 mM fenofibrate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profiles were significantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were significantly reduced in linalool-fed mice. These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor.

Highlights

We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs
We investigated the effects of a mixture of L- and D-linalool on the PPAR␣dependent lipid metabolism because linalool occurs naturally as two isomeric forms that were both significantly effective
In the TR-fluorescence resonance energy transfer (FRET) assay, linalool displayed a dose-dependent induction of the recruitment of a PGC1␣ coactivator peptide to PPAR␣ ligand binding domain (LBD) (EC50 = 5.45 ␮M, Fig. 1C), suggesting that linalool could act as a PPAR␣ ligand to induce target gene transcription

Summary

Introduction

We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. The oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-dietfed C57BL/6J mice (31%, P < 0.05) and human apo E2 mice (50%, P < 0.05) and regulated hepatic PPAR␣ target genes. No such effects were seen in PPAR␣-deficient mice. The concentrations of saturated FAs were significantly reduced in linalool-fed mice These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor.—Jun, H-j., J.

Methods

Results

Conclusion