Metabolic syndrome, natural compounds and nuclear receptors – are there new targets?

Abstract

Roughly 10% of genes of the human genome, among them all 48 human nuclear receptors (NR), are druggable, meaning that the function of their gene products can be modulated by small molecules. The classes NR1I/NR1H comprise molecules which initially have been described as orphan NR. They are now recognized as lipid and drug sensing molecules. Unlike PPARs belonging to the NR1C subfamily which are activated by triglyceride derivatives Constitutive Androstane Receptor Receptor (CAR), Pregnane-X-Receptor (PXR), Farnesoid Receptor (FXR) and Liver-X-Receptor are activated by cholesterol derivatives, bile acids, steroids and bilirubin. A common functional feature of these NRs is induction of a wide range of detoxifying enzymes. NRs are intimately involved in regulation of lipid metabolism and/or they contribute to liver protection. LXRs activated by oxysterols play the most prominent role in regulation of metabolic disease. LXRs have been described as regulators of lipogenesis, of cholesterol and glucose homeostasis and of anti-inflammatory processes, all representing specific features of the metabolic syndrome. FXR upon activation by chenodesoxycholic acid participates in regulation of lipid, lipoprotein and glucose metabolism as well as in hepatic regeneration and hepatoprotection. PXR is activated by pregnane derivatives and together with CAR and FXR guides cholesterol and bile acid homeostasis. Because of the functional link of these NRs to disease they represent valuable drug targets, inlcuding for plant derived natural compounds. The paper presented here will summarize data on plant secondary metabolites modulating the function of these lipid sensos in relation to specific aspects of the metabolic syndrome. Keywords: metabolic syndrome, lipid sensing, nuclear receptor, FXR, LXR, PXR, CAR