title: Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response.
abstract: Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
authors.affiliation: Metabolism Section, Department of Medicine, University of California San Francisco, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA. kfngld@itsa.ucsf.edu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Feingold
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Judy
authors.initials: J
authors.lastname: Shigenaga
authors.forename: Art
authors.initials: A
authors.lastname: Moser
authors.forename: Carl
authors.initials: C
authors.lastname: Grunfeld
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D005260:Female; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006593:Hexokinase / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D008070:Lipopolysaccharides; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D006593:Hexokinase