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 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.
Highlights
Fatty acid oxidation provides energy in tissues with high metabolic demands
Having found that mRNA levels of PGC-1␣ are significantly reduced during the acute-phase response (APR), we determined the effect of the APR on the mRNA levels of ERR␣, which has been shown to be activated by PGC-1␣
We investigated whether the expression of medium-chain acylcoenzyme A dehydrogenase (MCAD) and its regulator ERR␣ are altered during the APR, a condition that is accompanied by decreased fatty acid oxidation
Summary
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. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1␣, ERR␣, and MCAD pathway is a general response during infection and inflammation. Inflammation, and trauma induce the acutephase response (APR) via the release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), and IL-6 [7] These cytokines, in turn, trigger signaling pathways and cause characteristic changes in lipid metabolism, including decreased hepatic fatty acid oxidation [7, 8]. Cooperative induction of PPAR␣ target genes by peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) raises the possibility that PGC-1␣ may play a role in the APR-induced suppression of fatty acid oxidation [12]. A recent study by Huss, Kopp, and Kelly [15] demonstrated that PGC-1␣ interacts with and coactivates ERR␣ and enhances the transcriptional activation of MCAD by ERR␣, suggesting the possibility that ERR␣ and the MCAD pathway are suppressed during the APR
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