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

We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time-resolved fl uorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPAR α . Linalool stimulation reduced cellular lipid accumulation regulating PPAR - responsive genes and signifi cantly induced FA oxidation, and its effects were markedly attenuated by silencing PPAR expression. In mice, 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 α target genes. However, no such effects were seen in PPAR α -defi cient mice. Transcriptome profi ling 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 fenofi brate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profi les were signifi cantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were signifi cantly reduced in linalool-fed mice. These fi ndings suggest that the appropriate intake of a natural aromatic compound could exert benefi cial metabolic effects by regulating a cellular nutrient sensor.