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

• Published in: Journal of lipid research 2014-06, Vol.55 (6), p.1098-1110
• Main Authors: Jun, Hee-jin, Lee, Ji Hae, Kim, Jiyoung, Jia, Yaoyao, Kim, Kyoung Heon, Hwang, Kwang Yeon, Yun, Eun Ju, Do, Kyoung-Rok, Lee, Sung-Joon
• Format: Article
• Language: English
• Subjects: Acyclic Monoterpenes; agonist; Animals; Hepatocytes - metabolism; linalool; Liver - metabolism; Male; Metabolome - drug effects; Mice; Mice, Mutant Strains; Monoterpenes - pharmacology; peroxisome proliferator-activated receptor-α; PPAR alpha - agonists; PPAR alpha - biosynthesis; PPAR alpha - genetics; Transcriptome - drug effects; triglyceride; Triglycerides - blood; Triglycerides - genetics
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M045807

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.