Nuclear receptors as drug targets for metabolic disease

Abstract

Nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that control development, differentiation, and homeostasis. Over the last 15 years a growing number of nuclear receptors have been identified that coordinate genetic networks regulating lipid metabolism and energy utilization. Several of these receptors directly sample the levels of metabolic intermediates including fatty acids and cholesterol derivatives and use this information to regulate the synthesis, transport, and breakdown of the metabolite of interest. In contrast, other family members sense metabolic activity via the presence or absence of interacting proteins. The ability of these nuclear receptors to impact metabolism will be discussed and the challenges facing drug discovery efforts for this class of targets will be highlighted.

Figure 1. LXR activity in Macrophages

Activation of LXR in macrophages promotes reverse cholesterol transport via induction of ABCA1 and ABCG1, inhibits ER stress via activation of SREBP1c and SCD-1 and inhibits inflammation by repression of NFκβ.

Figure 2. LXR activity in the liver

Activation of LXR in the liver results in the up-regulation of ABCG5, ABCG8, and Cyp7A1 promoting the excretion and catabolism of cholesterol. Induction of Idol leads to enhanced degradation of the LDL receptor and decreased cholesterol uptake. Finally, induction of SREBP1c leads to increased fatty acid and triglyceride production.