Toll-Like Receptor-Mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism by Repressing Peroxisome Proliferator-Activated Receptor γ Coactivator-1 Signaling

Background-Currently, there are no specific therapies available to treat cardiac dysfunction caused by sepsis and other chronic inflammatory conditions. Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) is an early event in Gram-negative bacterial sepsis, triggering a robust inflammatory response and changes in metabolism. Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) alpha and beta serve as critical physiological regulators of energy metabolic gene expression in heart. Methods and Results-Injection of mice with LPS triggered a myocardial fuel switch similar to that of the failing heart: reduced mitochondrial substrate flux and myocyte lipid accumulation. The LPS-induced metabolic changes were associated with diminished ventricular function and suppression of the genes encoding PGC-1 alpha and beta, known transcriptional regulators of mitochondrial function. This cascade of events required TLR4 and nuclear factor-kappa B activation. Restoration of PGC-1 beta expression in cardiac myocytes in culture and in vivo in mice reversed the gene regulatory, metabolic, and functional derangements triggered by LPS. Interestingly, the effects of PGC-1 beta overexpression were independent of the upstream inflammatory response, highlighting the potential utility of modulating downstream metabolic derangements in cardiac myocytes as a novel strategy to prevent or treat sepsis-induced heart failure. Conclusions-LPS triggers cardiac energy metabolic reprogramming through suppression of PGC-1 coactivators in the cardiac myocyte. Reactivation of PGC-1 beta expression can reverse the metabolic and functional derangements caused by LPS-TLR4 activation, identifying the PGC-1 axis as a candidate therapeutic target for sepsis-induced heart failure. (Circ Heart Fail. 2011; 4: 474-482.)