Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm

Kenneth R. Feingold, Arthur Moser, Sophie M. Patsek, Judy K. Shigenaga, and Carl Grunfeld

Medicine, VA Medical Center, San Francisco, CA 94121

Corresponding Author: kenneth.feingold{at}ucsf.edu

Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid oxidation is an important source of ATP. Fatty acid oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis. Here we demonstrate that LPS decreases fatty acid oxidation and the expression of LPL, FATP1, CD36, CPT-1, MCAD and ACS, key proteins required for fatty acid uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPAR and /, RXR, , and , thyroid hormone receptor and , and ERR and their co-activators PGC-1, PGC-1, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPAR deficient mice, baseline CPT-1 and FATP-1 levels were markedly decreased and were not further reduced by LPS suggesting that a decrease in the PPAR signaling pathway plays an important role in inducing some of these changes. The decrease in fatty acid oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.

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