Role of TNF-α receptor 1 signaling on downregulation of intestinal P-glycoprotein by high-fat diet in mice

BARRANCO, MARIA MANUELA; PERDOMO, VIRGINIA GABRIELA; ZECCHINATI, FELIPE; MANARIN, ROMINA; MASSUH, GRETA; SIGAL, NICOLAS; VIGNADUZZO, SILVANA; MOTTINO, AD; VILLANUEVA, SILVINA STELLA MARIS; GARCÍA, FABIANA

Congreso; SAFIS+ALAF JOINT MEETING; 2021

Obesity is characterized by a proinflammatory state with increased cytokines levels and metabolic disorders, one of the pathways involved in these alterations is mediated by tumor necrosis factor alpha (TNF-α) through its receptor 1 (TNFR1). Patients with metabolic disorders take medicaments that are initially subjected to intestinal metabolism and disposition. P-glycoprotein (P-gp) is a relevant component of the intestinal transcellular barrier, with maximum expression at the level of the ileum, which decreases the absorption of toxic xenobiotics and orally incorporated therapeutic drugs, thus modulating their bioavailability. The aim of this study was to evaluate the effect of a high-fat diet (HFD, 40% fat for 16 weeks) on intestinal P-gp mRNA expression and activity in wild-type male C57BL/6 (C57, 5 weeks old, n: 20) mice and knockout mice for TNFR1 (R1KO, 5 weeks old, n: 20) to delineate a possible role of TNF-α signaling. For the statistical comparison we used t-student or one-way ANOVA followed by the post hoc Tukey test. The results were expressed as % of C57-Control group. All mice fed with HFD increased their weight and adipose mass, in addition to hypercholesterolemia and hyperglyceridemia. Only the C57-HFD group presented hyperglycemia and insulin resistance. Ileal mRNA expression of P-gp was 62% lower in C57-HFD than in control animals. This result correlated well with a 48% decrease in the apical transport rate of the P-gp substrate, Rhodamine 123, in everted intestinal sacs. In contrast, HFD did neither modify the intestinal P-gp expression or activity in R1KO mice. Besides, C57-HFD mice showed an ileal inflammatory milieu consisting of elevated TNF-α mRNA levels, whereas in R1KO mice this cytokine was not detectable with either diet. Herein, we demonstrate an impairment of the P-gp barrier function induced by HFD in mice, with the inflammatory response mediated by TNF-α receptor 1 signaling likely involved.