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Journal of Lipid Research, Vol. 50, 2055-2063, October 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Kenneth R. Feingold¹, Arthur Moser, Sophie M. Patzek, Judy K. Shigenaga and Carl Grunfeld

Metabolism Section, Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121

¹ To whom correspondence should be addressed. e-mail: 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 (FA) oxidation is an important source of ATP. FA 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 lipopolysaccharide (LPS) decreases FA oxidation and the expression of lipoprotein lipase (LPL), FA transport protein 1 (FATP-1), CD36, carnitine palmitoyltransferase beta, medium chain acyl-CoA dehydrogenase (MCAD), and acyl-CoA synthetase, key proteins required for FA uptake and oxidation, in the diaphragm. LPS also decreased mRNA levels of PPAR and β/, RXR, β, and , thyroid hormone receptor and β, and estrogen related receptor alpha (ERR) and their coactivators PGC-1, PGC-1β, SRC1, SRC2, Lipin 1, and CBP. Zymosan resulted in similar changes in the diaphragm. Finally, in PPAR deficient mice, baseline CPT-1β 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 FA oxidation in the diaphragm may be detrimental, leading to decreased diaphragm contraction and an increased risk of respiratory failure during sepsis.

Supplementary key words acute phase • thyroid hormone receptor • carnitine palmitoyltransferase I • fatty acid transport proteins

Abbreviations: ACC, acetyl CoA carboxylase; ACS, acyl-CoA synthetase; AGPAT, 1-acyl-glycerol-3-phosphate acyltransferase; Atp5g1, ATP synthase; H⁺ transporting, mitochondrial FO complex, subunit c; CBP, CREB binding protein; Cox 5a, cytochrome c oxidase, subunit 5a; CPT-1β, carnitine palmitoyltransferase beta; ERR, estrogen-related receptor alpha; FATP-1, FA transport protein 1; GPAT, glycerol-3-phosphate acyltransferase; HK1, hexose kinase 1; HK2, hexose kinase 2; Idh3a, isocitrate dehyrogenase 3 (NAD⁺) alpha; LPS, lipopolysaccharide; MCAD, medium chain acyl-CoA dehydrogenase; Nduf58, NADH dehydrogenase (ubiquinone) Fe-S protein 8; PDK4, pyruvate dehydrogenase kinase isoenzyme 4; PGC-1, peroxisome proliferator-activated receptor gamma coactivator-1; SAA, serum amyloid A; SRC1, steroid receptor coactivator-1; TNF-, tumor necrosis factor-alpha; TRAP, thyroid receptor-associated protein

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