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Farnesol inhibits fatty acid synthase expression and activity via a 9‐cis retinoic acid‐dependent mechanism
Author(s) -
Duncan Robin Elaine,
Archer Michael C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1000-c
Subject(s) - farnesol , retinoic acid , receptor , retinoid x receptor , fatty acid synthase , biology , nuclear receptor , biochemistry , chemistry , medicine , endocrinology , fatty acid , transcription factor , gene
Farnesol is a metabolite of the mevalonate/cholesterol biosynthetic pathway that is produced endogenously in cells and is also present in dietary fruits and vegetables. Recently, farnesol has been shown to inhibit de novo triglyceride synthesis in hepatocytes although the molecular mechanism mediating this effect has not been reported. We treated MCF‐7 human breast cancer cells and rat hepatocytes with farnesol and found decreased fatty acid synthase (FAS) activity that was mediated by lower mRNA and protein levels. Farnesol has previously been shown to regulate activity of the farnesoid X receptor, peroxisome proliferator‐activated receptor alpha and thyroid hormone receptor beta 1. We investigated whether regulation of these nuclear hormone receptors may mediate effects of farnesol on FAS mRNA expression in rat hepatocytes but found no evidence of regulation through these transcription factors. We did, however, observe a complete restoration of FAS mRNA levels in cells treated concomitantly with farnesol and 9‐cis retinoic acid (RA), while treatment of control cells with 9‐cis RA alone had no effect. Although decreased retinoid X receptor (RXR) beta protein levels were apparent by 48 h in cells treated with farnesol, this could not explain effects of farnesol on FAS that were observed already by 24 h. We conclude that farnesol inhibits FAS at the level of transcription and that this effect appears to be mediated by decreased RXR activation.