Intestine-Specific Deletion of Microsomal Triglyceride Transfer Protein Increases Mortality in Aged Mice

• Type of Material: Article
• Authors: Zhe Liang, Emory University; Yan Xie, Washington University School of Medicine; Jessica A. Dominguez, Bastyr University; Elise R. Breed, Emory University; Benyam P. Yoseph, Emory University; Eileen Burd, Emory University; Alton B Farris III, Emory University; Nicholas O. Davidson, Washington University School of Medicine; Craig Coopersmith, Emory University
• Language: English
• Date: 2014
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Liang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0101828
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 7
• Start Page: e101828
• End Page: e101828
• Grant/Funding Information: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by funding from National Institutes of Health (GM072808, GM104323, GM095442, GM66202, HL-38180, DK-56260, DK-52574) and the Shock Society Early Career Investigator Fellowship.
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Background Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8–10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. Methods Aged (20–24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. Results In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. Conclusions Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.