Soybean Oil-Based Lipid Emulsion Increases Intestinal Permeability of Lipopolysaccharide in Caco-2 Cells by Downregulation of P-Glycoprotein via ERK-FOXO 3a Pathway.
OBJECTIVE
Elevated intestinal permeability of lipopolysaccharide (LPS) is a major complication for patients with parenteral nutrition (PN), but the pathogenesis is poorly understood. Intestinal P-glycoprotein (P-gp) is one of the efflux transporters that contribute to restricting the permeability of lipopolysaccharide via transcellular route. P-gp expression may be regulated by PN ingredients, and thus this study sought to investigate the effect of PN on the expression of P-gp and to elucidate the underlying mechanism in vitro.


METHODS
Caco-2 cells were treated with PN ingredients. Changes in P-gp expression and function were determined and the role of ERK-FOXO 3a pathway was studied. Transport studies of FITC-lipopolysaccharide (FITC-LPS) across Caco-2 cell monolayers were also performed.


RESULTS
Among PN ingredients, soybean oil-based lipid emulsion (SOLE) exhibited significant inhibitory effect on P-gp expression and function. This regulation was mediated via activation of ERK pathway with subsequent nuclear exclusion of FOXO 3a. Importantly, P-gp participated in antagonizing the permeation of FITC-LPS (apical to basolateral) across Caco-2 cell monolayers. SOLE significantly increased the permeability of FITC-LPS (apical to basolateral), which was associated with impaired P-gp function.


CONCLUSIONS
The expression and function of intestinal P-gp is suppressed by SOLE in vitro.
Xin Hua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jun-Kai
JK
Yan
Jie
J
Zhu
Bei-Lin
BL
Gu
Wei-Hui
WH
Yan
Yong-Tao
YT
Xiao
Ke-Jun
KJ
Zhou
Jie
J
Wen
Yang
Y
Wang
Wei
W
Cai
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004655:Emulsions; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000819:agonists / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D013024:Soybean Oil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004655:Emulsions; C499517:FOXO3 protein, human; D005456:Fluorescent Dyes; D000071316:Forkhead Box Protein O3; D008070:Lipopolysaccharides; D013024:Soybean Oil; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016650:Fluorescein-5-isothiocyanate