Suppression of estrogen-related receptor α and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response

Abstract

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 acylcoenzyme A dehydrogenase (MCAD), its regulator the estrogen-related receptor α (ERRα), and a key coactivator of ERRα, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). mRNA levels of PGC-1α, ERRα, 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 ERRa 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 ERRα by supershift with antibody to ERRα. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1α, ERRα, 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.