Skeletal muscle as a target of LXR agonist after long-term treatment: focus on lipid homeostasis

The liver X receptors (LXR)alpha and LXR beta are transcription factors belonging to the nuclear receptor family, which play a central role in metabolic homeostasis, being master regulators of key target genes in the glucose and lipid pathways. Wild- type (WT), LXR alpha(-/-), and LXR beta(-/-) mice were fed a chow diet with (treated) or without (control) the synthetic dual LXR agonist GW3965 for 5 wk. GW3965 raised intrahepatic triglyceride (TG) level but, surprisingly, reduced serum TG level through the activation of serum lipase activity. The serum TG reduction was associated with a repression of both catecholamine- stimulated lipolysis and relative glucose incorporation into lipid in isolated adipocytes through activation of LXR beta. We also demonstrated that LXR alpha is required for basal (nonstimulated) adipocyte metabolism, whereas LXR beta acts as a repressor of lipolysis. On the contrary, in skeletal muscle (SM), the lipogenic and cholesterol transporter LXR target genes were markedly induced in WT and LXR alpha(-/-) mice and to a lesser extent in LXR beta(-/-) mice following treatment with GW3965. Moreover, TG content was reduced in SM of LXR beta(-/-) mice, associated with increased expression of the main TG-lipase genes Hsl and Atgl. Energy expenditure was increased, and a switch from glucose to lipid oxidation was observed. In conclusion, we provide evidence that LXR might be an essential regulator of the lipid balance between tissues to ensure appropriate control of the flux of fuel. Importantly, we show that, after chronic treatment with GW3965, SM becomes the target tissue for LXR activation, as opposed to liver, in acute treatment.