Upregulation of Farnesoid X Receptor expression and activity in colonic epithelial cells by a lipid-based plant extract

Introduction: The nuclear bile acid receptor, farnesoid X receptor (FXR), is a critical regulator of colonic epithelial transport and barrier function. Downregulated expression of the receptor is associated with ulcerative colitis (UC) and colorectal cancer (CRC), while studies in animal models show FXR activation to be protective in these conditions. Previous studies have also shown certain plant-derived extracts to be protective against the development of colonic inflammation and cancer, while others have shown that phytochemicals present within such extracts have the capacity to act as ligands of FXR. With this in mind, the current study set out to investigate the potential for using dietary plant extracts to modulate FXR activity in colonic epithelial cells. Methods: A lipid extract (designated QE2) was prepared by supercritical CO2 extraction from a dietary plant grain ( identity withheld ). Studies were carried out on T84 colonic epithelial cells grown as polarised monolayers on semipermeable supports. FXR expression was measured by RT-PCR and Western blotting, while activity was assessed by measuring basolateral secretion of the FXR target protein, FGF-19, by ELISA. Results: Apical treatment of T 84 cells with QE2 alone (24 hrs) was without effect on FGF-19 mRNA expression or protein secretion, indicating naturally-occurring agonists of the receptor were not present in the extract. However, QE2 (6 – 24 hrs) potently increased mRNA expression of FXR to 9.95 ± 2.8 fold of that in control cells (n = 7; p < 0.05). Furthermore, QE2 treatment enhanced FGF-19 secretion in response to subsequent exposure to the FXR agonist, GW4064 (5 μM), to 144.8 ± 31.1 pg/ml compared to 29.3 ± 7.7 pg/ml in cells treated with GW4064 alone (n = 6; p = 0.01). HPLC analysis of the lipid extract revealed it to predominantly contain the polyunsaturated fatty acids (PUFAs), a-linolenic acid (ALA, 41%) and linoleic acid (LA, 52%). Similar to QE2, treatment of T 84 cells with ALA enhanced FXR mRNA and protein expression to 11.43 ± 2.1 fold (n = 7, p < 0.01) and 6.4 ± 1.2 fold (n = 6, p < 0.05) of that in untreated cells, respectively. ALA treatment also enhanced the effects of GW4064 on both mRNA and protein expression of FGF19 by 4.4 ± 1.6 (n = 7) and 6.5 ± 1.4 fold (n = 8, p < 0.05), respectively. LA exerted similar effects on FXR expression and activity (data not shown). Treatment with ALA (3 hrs) also increased expression of the PPAR target gene, ANGPTL4, to 66.3 ± 9.5 fold (n = 7; p < 0.01) of that in untreated cells. Furthermore, the effects of ALA on FXR were mimicked by the PPARγ and PPARα agonists, rosiglitazone (1 μM) and WY14643 (10 μM), respectively. Finally, the PPARγ and PPARα antagonists, GW9662 (20 µM) and GW6471 (1 µM), both inhibited ALA-induced FXR mRNA expression to 0.5 ± 0.1 fold (n = 11; p < 0.001) and 0.29 ± 0.1 fold (n = 4; p < 0.05) of that in control cells, respectively. Conclusion: These data indicate that lipid-based plant extracts have the capacity to enhance FXR expression and activity in colonic epithelial cells and that this effect is likely mediated, at least in part, by PUFAs acting through PPARs. Our findings suggest that dietary plant extracts containing PUFAs have potential for development as a new class of “FXR-targeted nutraceutical” for the treatment and prevention of UC ad CRC. This work was supported by an Investigator Award (Grant #: 16-A-4445) from Science Foundation Ireland. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.