Abstract
High-fat diet (HFD) feeding disrupts the intestinal barrier integrity, inducing the translocation of bacteria into the portal circulation, leading to the whole-body inflammation. Intestinal epithelial cells (IEC), producing antimicrobial proteins to prevent the attachment and entry of pathogens, are affected by the tissue hypoxia. The hypoxia-inducible factor (HIF)-1α is pivotal in the transcriptional response to oxygen flux. PURPOSE: To determine the role of HIF-1α signaling pathway in the regulation of intestinal barrier function on HFD fed mice. METHODS: The Villin-Cre mediated, IEC-specific deletion of Hif1a (Hif1aVKO) and the control Hif1afl/fl mice (male, 8-week) were used in this study. The Hif1aVKO and Hif1afl/fl were fed HFD (HFD-Hif1aVKO and HFD-Hif1afl/fl, n=6/group) or normal chow for 12 weeks. Immediately after euthanasia, the serum, abdominal fat, intestine and feces were sampled. The intestinal mucus structure was observed by the AB-PAS staining. The intestinal permeability was quantified with FITC-dextran. Fasting plasma glucose, albumin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, triglycerides (TG), total cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol levels were measured. The fecal microbial DNA was extracted and sequenced on an Illumina MiSeq platform. Student's t-tests and one-way ANOVA were used. Differences with P<0.05 were considered significant. All animal experiments were performed in compliance with and approved by the Shanghai University of Sport ethical review board. RESULTS: We found that HFD feeding markedly increase the intestinal permeability without significant morphological changes. Compare with HFD-Hif1afl/fl, the HFD-Hif1aVKO mice were higher in the body weight (40.55±3.94 vs. 35.06±5.31 g, p<0.05), TG (1.75±0.56 vs. 1.08±0.31 mmol/l, p<0.05), TC(4.28±0.92 vs. 3.74±0.56, p<0.05) and LDL-C(0.83±0.08 vs. 0.68±0.14, p<0.05). Principal coordinates analysis based on unweighted Unifrac distances highlighted a clear clustering of the microbial populations of Hif1aVKO away from that of Hif1afl/fl. CONCLUSIONS:IEC HIF-1α signaling is involved in the intestinal barrier function maintenance in HFD fed mice. Supported by the National Natural Science Foundation of China (31701040, 31801003 and 31471135).
Published Version
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