Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets.

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Zhao A, Yu J, Lew JL, Huang L, Wright SD, Cui J

Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets.

DNA Cell Biol. 2004 Aug;23(8):519-26.

PubMed ID

15307955 [ View in PubMed

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Abstract

Polyunsaturated fatty acids (PUFAs) have been previously reported as agonists of peroxisome proliferatoractivated receptor and antagonists of the liver X receptor. The activities on these two nuclear receptors have been attributed to their beneficial effects such as improvement of dyslipidemia and insulin sensitivity and decrease of hepatic lipogenesis. Here we report that PUFAs are ligands of farnesoid X receptor (FXR), a nuclear receptor for bile acids. In a conventional FXR binding assay, arachidonic acid (AA, 20:4), docosahexaenoic acid (DA, 22:6), and linolenic acid (LA, 18:3) had an affinity of 2.6, 1.5, and 3.5 microM, respectively. In a cell-free coactivator association assay, AA, DA, and LA decreased FXR agonist-induced FXR activation with IC(50)s ranging from 0.9 to 4.7 microM. In HepG2 cells, PUFAs regulated the expression of two FXR targets, BSEP and kininogen, in an opposite fashion, although both genes were transactivated by FXR. All three PUFAs dose-dependently enhanced FXR agonist-induced BSEP expression but decreased FXR agonist-induced human kininogen mRNA. Saturated fatty acids such as stearic acid (SA, 18:0) and palmitic acid (PA, 16:0) did not bind to FXR and did not change BSEP or kininogen expression. The pattern of BSEP and kininogen regulation by PUFAs is closely similar to that of the guggulsterone, previously reported as a selective bile acid receptor modulator. Our results suggest that PUFAs may belong to the same class of FXR ligands as guggulsterone, and that the selective regulation of FXR targets may contribute to the beneficial effects of PUFAs in lipid metabolism.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arachidonic Acid	Bile acid receptor	Protein	Humans	Unknown	Ligand	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
alpha-Linolenic acid	Approved Investigational Nutraceutical	CPT1A	1374	upregulated	alpha-Linolenic Acid results in increased expression of CPT1A mRNA	11q13.3
Arachidonic Acid	Experimental	CPT1A	1374	upregulated	Arachidonic Acid results in increased expression of CPT1A mRNA	11q13.3