Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

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.

• Authors: Zhe Liang, Yan Xie, Jessica A Dominguez, Elise R Breed, Benyam P Yoseph, Eileen M Burd, Alton B Farris, Nicholas O Davidson, Craig M Coopersmith
• Journal: PloS one (PLoS One) Vol. 9 Issue 7 Pg. e101828 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25010671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cytokines
• Triglycerides
• microsomal triglyceride transfer protein
• Cholesterol
• Peroxidase

Topics

• Aging (genetics, metabolism)
• Animals
• Apoptosis
• Biological Transport
• Carrier Proteins (genetics)
• Cell Proliferation
• Cholesterol (metabolism)
• Cytokines (metabolism)
• Gene Knockout Techniques
• Intestinal Mucosa (metabolism, pathology)
• Intestines (pathology)
• Liver (immunology)
• Lung (metabolism)
• Mice
• Organ Specificity
• Peroxidase (metabolism)
• Pseudomonas aeruginosa (physiology)
• Sepsis (metabolism, mortality, pathology, physiopathology)
• Spleen (immunology)
• Survival Analysis
• Triglycerides (metabolism)