DOWNREGULATION OF INTESTINAL MULTIDRUG RESISTANCE PROTEIN 2 IN OBESE MICE IS REGULATED INDEPENDENTLY OF CYTOKINES PROFILE

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

MAR DE PLATA

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

The inflammatory response generated in obesity is mediated by different cytokines which determined most of the metabolic alterations associated with this disease. The Multidrug resistance protein 2 (Mrp2) and P-glycoprotein (P-gp) efflux pumps involved in the intestinal biochemical barrier, are altered in inflammatory states. Previous studies from our group, demonstrated the involvement of the Tumor Necrosis Factor-alpha receptor 1 (TNFR1) signaling pathway in the downregulation of ileal P-gp from obese mice. Therefore, the aim of this study was to evaluate the mRNA expression and activity of jejunal Mrp2 in wild-type male mice C57BL/6 (C57, 5 weeks old, n: 20) and knockout mice for TNFR1 (R1KO, 5 weeks old, n: 20) subjected to a high-fat diet (HFD, 40% fat) for 16 weeks and to investigate the intestinal cytokines profile developed. The statistical comparisons were done by t-student or one-way ANOVA followed by post-test. Results were expressed as % of C57 or R1KO-Control.All mice fed with HFD increased their weight and adipose mass, also showed higher cholesterolemia and triglyceridemia levels respect to controls. Only the C57-HFD group presented increased glycemia levels and insulin resistance. The HFD decreased the mRNA expression of Mrp2, both in C57 (-42%) and R1KO (-66%) mice when comparing to their respective control group. These result correlated well with the 53% and 56% decrease respectively, in the apical transport rate of DNP-SG, in everted intestinal sacs from each HFD group. When evaluating the intestinal cytokines profile from C57-HFD mice, we observed an increase in TNF-α (+52%), IL-6 (+158%) and a decrease in IFN-γ (-88%) levels. However in the R1KO-HFD mice, there were not intestinal expression of TNF-α, with decreased IFN-γ (-77%) and without changes in IL-6 levels. We conclude that the downregulation in the expression and activity of intestinal Mrp2 by the high-fat diet, is regardless of the main intestinal proinflammatory cytokines developed.