Induction of the intestinal membrane transporters ABCA1 and ABCG8 by 27-hydroxycholesterol through a redox mechanism

in Redox Experimental Medicine
Authors:
Noemi Iaia N Iaia, Clinical and Biological Sciences , University of Turin, Orbassano (Turin), Italy

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Valerio Leoni V Leoni, Laboratory of Clinical biochemistry, ASST-Brianza, University of Milan-Bicocca Department of Medicine and Surgery, Desio , Italy

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Giuseppe Poli G Poli, Clinical and Biological Sciences, University of Turin School of Medicine, Orbassano, Italy

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Fiorella Biasi F Biasi, Department of Clinical and Biological Sciences, University of Turin, Torino, 10124, Italy

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Correspondence: Fiorella Biasi, Email: fiorella.biasi@unito.it
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Objective.

We tested the effect of 27-hydroxycholesterol (27OHC) on the expression and synthesis of two membrane transporters involved in sterols extrusion from intestinal epithelium into the gut lumen: ATP binding cassette A1 (ABCA1) and G8 (ABCG8). Special attention was given to ABCG8, a key player in the intestinal cell discharge of plant sterols.

Methods.

Differentiated CaCo-2 intestinal cells were supplemented with 27OHC, added to the cell incubation medium at the final concentration of 1 or 5 µM. These 27OHC externally added amounts were proven to reach intracellular oxysterol levels within the range of those normally recovered in the human peripheral blood.

Results.

An up-regulation of the ABCA1 and ABCG8 mRNAs was observed in the CaCo-2 cells supplemented with 27OHC. Moreover, both 1 µM and 5 µM 27OHC induced a net, and steady, statistically significant, increase of both ABCA1 and ABCG8 protein levels. Of interest, the cellular pre-treatment with diphenylene iodonium (DPI), a selective inhibitor of NADPH oxidase, i.e. a major intracellular source of reactive oxygen species (ROS), totally inhibited the 27OHC enhancement of both ABCA1 and ABCG8 protein synthesis.

Conclusions.

This in vitro study shows for the first time that the addition of 27OHC to intestinal epithelial cells up-regulates ABCG8, the transporter discharging plant sterols into the gut lumen, besides confirming to induce ABCA1 as well. Importantly, the 27OHC-dependent up-regulation of the two transporters appears to involve a redox mechanism rather than the canonical liver-X-receptors (LXRs)-dependent pathway.

Significance.

The 27OHC introduced with the diet might modulate the plant sterol extrusion in the gut, in parallel with that of cholesterol.

 

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