PPARα-LXR as a novel metabolostatic signalling axis in skeletal muscle that acts to optimize substrate selection in response to nutrient status

LXR (liver X receptor) and PPAR alpha (peroxisome-proliferator-activated receptor alpha) are nuclear receptors that control the expression of genes involved in glucose and lipid homoeostasis. Using wild-type and PPAR alpha-null mice fed on an LXR-agonist-supplemented diet, the present 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 (stearoyl-CoA desaturase 1) expression and down-regulating PGC-1 alpha (PPAR gamma co-activator-1 alpha) and PDK4 (pyruvate dehydrogenase kinase 4) expression. PPAR alpha deficiency enhanced LXR stimulation of SCD1 expression, and facilitated elevated SREBP-1 (sterol-regulatory-element-binding protein-1) expression. However, LXR-mediated down-regulation of PGC-1 alpha and PDK4 was opposed and reversed by PPAR alpha deficiency. During fasting, prior LXR activation augmented PPAR alpha signalling to heighten FA (fatty acid) oxidation and decrease glucose oxidation by augmenting fasting-induced up-regulation of PGC-1 alpha and PDK4 expression, effects opposed by PPAR alpha deficiency. Starvation-induced down-regulation of SCD1 expression was opposed by antecedent LXR activation in wild-type mice, an effect enhanced further by PPAR alpha deficiency, which may elicit increased channelling of FA into triacylglycerol to limit lipotoxicity. Our results also identified potential regulatory links between the protein deacetylases SIRT1 (sirtuin I) and SIRT3 and PDK4 expression in muscle from fasted mice, with a requirement for PPAR alpha. In summary, we therefore propose that a LXR-PPAR alpha signalling axis acts as a metabolostatic regulatory mechanism to optimize substrate selection and disposition in skeletal muscle according to metabolic requirement.