PPARalpha-LXR as a novel metabolostatic signaling axis in skeletal muscle which acts to optimize substrate selection in response to nutrient status

Overview & Synopsis

Liver X Receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) alpha are nuclear receptors that control expression of genes involved in glucose and lipid homeostasis. Using wild type and PPARalpha-null mice fed an LXR agonist-supplemented diet, the study analysed the impact of pharmacological LXR activation on the expression of metabolically-important genes in skeletal muscle, testing the hypothesis that LXR activation can modulate PPAR action in skeletal muscle in a manner dependent on nutritional status. In the fed state, LXR activation promoted a gene profile favouring lipid storage and glucose oxidation, increasing SCD1 expression and downregulating PGC-1alpha and PDK4 expression. PPARalpha deficiency enhanced LXR stimulation of SCD1 expression, and facilitated elevated SREBP1 expression. However, LXR-mediated downregulation of PGC-1alpha and PDK4 was opposed and reversed by PPARalpha deficiency. During fasting, prior LXR activation augmented PPARalpha signaling to heighten fatty acid oxidation and decrease glucose oxidation by augmenting fasting-induced upregulation of PGC-1alpha and PDK4 expression, effects opposed by PPARalpha deficiency. Starvation-induced downregulation of SCD1 expression was opposed by antecedent LXR activation in wild-type mice, an effect further enhanced by PPARalpha deficiency, which may elicit increased channeling of FA into TAG to limit lipotoxicity. Our data also identified potential regulatory links between the protein deacetylases SIRT1 and SIRT3 and PDHK4 expression in fasted muscle, with a requirement for PPARalpha. In summary, we therefore propose that a LXR-PPARa signaling axis acts as a metabolostatic regulatory mechanism to optimize substrate selection and disposition in skeletal muscle according to metabolic requirement.