Suppression of estrogen-related receptor alpha and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response.
Fatty acid oxidation provides energy in tissues with high metabolic demands. During the acute-phase response (APR) induced by infection and inflammation, fatty acid oxidation is decreased associated with hypertriglyceridemia. Little is known about the mechanism by which the APR decreases fatty acid oxidation. Therefore, we investigated whether the APR affects the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD), its regulator the estrogen-related receptor alpha (ERRalpha), and a key coactivator of ERRalpha, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). mRNA levels of PGC-1alpha, ERRalpha, and MCAD are markedly reduced in the liver, heart, and kidney of mice during the lipopolysaccharide (LPS)-induced APR. The decreases were rapid and occurred at very low doses of LPS. MCAD activity in liver was also reduced. Furthermore, binding of hepatic nuclear extracts to the ERRalpha response element found in the promoter region of MCAD was significantly decreased during the APR, suggesting the decreased transcription of the MCAD gene. The binding activity was identified as ERRalpha by supershift with antibody to ERRalpha. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1alpha, ERRalpha, and MCAD pathway is a general response during infection and inflammation. Our study provides a potential mechanism by which the APR decreases fatty acid oxidation.
Kim
Min Sun
MS
Department of Medicine, University of California San Francisco, and Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Shigenaga
Judy K
JK
Moser
Arthur H
AH
Feingold
Kenneth R
KR
Grunfeld
Carl
C
D000210:Acute-Phase Reaction / Q000503:physiopathology*; D042964:Acyl-CoA Dehydrogenase / Q000096:biosynthesis*; D000818:Animals; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors; D014425:Turpentine / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology; D000097983:ERRalpha Estrogen-Related Receptor
D042964:Acyl-CoA Dehydrogenase; D005227:Fatty Acids; D008070:Lipopolysaccharides; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D014425:Turpentine; D015054:Zymosan; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse