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Farnesol Decreases Serum Triglycerides in Rats: Identification of Mechanisms Including Up-Regulation of PPARα and Down-Regulation of Fatty Acid Synthase in Hepatocytes

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Lipids

Abstract

Obesity is associated with impaired fatty acid (FA) oxidation and increased de novo hepatic lipogenesis that may contribute to the development of hypertriglyceridemia, an important risk factor for the development of cardiovascular disease. Strategies to improve hepatocyte FA metabolism, including dietary interventions, are therefore important for the prevention of obesity-associated co-morbidities. Farnesol is consumed in the diet as a component of plant products. In the present study, we administered farnesol orally to rats for seven days and found significantly reduced serum triglyceride concentrations compared with controls. Potential mechanisms underlying the hypotriglyceridemic effect of farnesol were investigated using clone-9 cultured rat hepatocytes. Farnesol significantly upregulated expression of peroxisome proliferator-activated receptor alpha (PPARα) and the PPARα-regulated genes fatty acyl-CoA oxidase and carnitine palmitoyl transferase 1a, suggesting that increased hepatic FA oxidation may contribute to serum triglyceride lowering in rats. Farnesol did not change SREBP-1c mRNA levels, but significantly down-regulated fatty acid synthase (FAS) mRNA and protein levels and activity, indicating that attenuated lipogenesis may also contribute to hypotriglyceridemic effects of farnesol in vivo. Rescue experiments revealed that down-regulation of FAS by farnesol was not related to activation of PPARα, but rather was caused by a 9-cis retinoic acid mediated mechanism that involved down-regulation of retinoid X receptor β. Diets rich in plant products are associated with a lower risk of cardiovascular disease. Our findings suggest that farnesol may contribute to this protective effect by lowering serum TG levels.

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Abbreviations

ACOX:

Fatty acyl-CoA oxidase

CPT-1a:

Carnitine palmitoyl transferase 1a

FA:

Fatty acid

FAS:

Fatty acid synthase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

PPARα:

Peroxisome-proliferator activated receptor alpha

RXRα:

Retinoid X receptor alpha

RXRβ:

Retinoid X receptor beta

SREBP-1c:

Sterol regulatory element binding protein-1

TG:

Triglycerides

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Acknowledgments

This work was supported by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada. R.E.D. is a recipient of an NSERC postdoctoral fellowship. The authors would like to thank Chris Lange for assistance.

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  1. Robin E. Duncan

    Present address: Department of Nutritional Sciences and Toxicology, University of California, 220 Morgan Hall, Berkeley, CA, 94720, USA

Authors and Affiliations

  1. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Fitzgerald Building, 150 College Street, Toronto, ON, M5S 3E2, Canada

    Robin E. Duncan & Michael C. Archer

  2. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 3E2, Canada

    Michael C. Archer

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  1. Robin E. Duncan
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Correspondence to Michael C. Archer.

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Duncan, R.E., Archer, M.C. Farnesol Decreases Serum Triglycerides in Rats: Identification of Mechanisms Including Up-Regulation of PPARα and Down-Regulation of Fatty Acid Synthase in Hepatocytes. Lipids 43, 619–627 (2008). https://doi.org/10.1007/s11745-008-3192-3

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  • DOI: https://doi.org/10.1007/s11745-008-3192-3

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