TLR4-Mediated Signals Converge on the PGC-1 Family of Nuclear Receptor Coactivators to Control Myocardial Metabolism and Function

Introduction: Heart failure (HF) is associated with myocardial inflammation and dysregulated metabolism. Toll-like Receptor 4 (TLR4) is activated by inflammatory stimuli such as lipopolysaccharide (LPS) leading to cytokine production and LV dysfunction. TLR4 has also been implicated in the pathogenesis of insulin resistance (IR), obesity, and HF. PGC-1α/β are inducible, cardiac enriched, transcriptional co-activators that regulate metabolism via interactions with nuclear receptors such as PPARα and ERRα. HF is associated with reduced PGC-1 signals. Hypothesis: TLR4-mediated inflammation modulates myocardial metabolism through PGC-1 co-activators. Results: Using an isolated working heart system to assess myocardial fuel utilization, we found that LPS decreased fatty acid oxidation (FAO) and glycolytic rates by 30% and 45%, respectively. LPS also triggered myocyte triglyceride (TG) accumulation, consistent with the observed decrease FAO capacity. PGC-1α/β, which serve as key regulators of FAO gene expression in heart, were rapidly downregulated by LPS. PGC-1 gene targets involved in FAO and mitochondrial respiration were also downregulated in a coordinated manner following LPS stimulation. In contrast, TLR4-/- mice did not exhibit LPS-mediated PGC-1 downregulation or myocyte TG accumulation. Using a myocyte specific, tetracycline inducible PGC-1β transgenic mouse (tet-on PGC-1β), PGC-1β induction prior to LPS administration reversed the effects of LPS on cardiac FAO and mitochondrial gene expression without altering cytokine levels. Myocardial TG accumulation induced by LPS was also significantly attenuated by forced expression of PGC-1β. Importantly, LPS-mediated LV dysfunction was rescued in tet-on PGC-1β mice (LV fractional shortening 40% vs. 25%), demonstrating the physiologic importance of these metabolic alterations. Conclusions: TLR4 activation leads to reduced expression of PGC-1α/β in the heart, which in turn triggers a cascade of metabolic changes characterized by decreased FAO capacity, myocyte TG accumulation, and LV dysfunction. Restoration of PGC-1β levels in the heart reverses the metabolic and functional alterations caused by this inflammatory insult. These data describe a novel PGC-1-mediated regulatory crosstalk mechanism between inflammatory signals and metabolism in the heart, a pathway that is relevant to the pathogenesis of HF.