PXR and 4β-Hydroxycholesterol Axis and the Components of Metabolic Syndrome

Abstract

Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesized to play an important role in metabolic disruption elicited by exposure to endocrine-disrupting chemicals. The majority of the data on the effects of PXR activation on metabolic health come from animal and cell culture experiments. However, randomized, placebo-controlled, human trials indicate that the treatment with PXR ligands impairs glucose tolerance and increases 24-h blood pressure and heart rate. In addition, plasma 4β-hydroxycholesterol (4βHC), formed under the control of PXR in the liver, is associated with lower blood pressure in healthy volunteers. Furthermore, 4βHC regulates cholesterol transporters in peripheral tissues and may activate the beneficial reverse HDL cholesterol transport. In this review, we discuss the current knowledge on the role of PXR and the PXR-4βHC axis in the regulation of components of metabolic syndrome.

Keywords: 4β-hydroxycholesterol; hyperglycemia; hypertension; metabolic syndrome; obesity; pregnane X receptor; reverse cholesterol transport.

Figure 1

Mechanisms mediating the effect of PXR activation on hepatic glucose uptake. In the postprandial state, GLUT2 glucose transporter facilitates glucose uptake into the hepatocytes. In the next step of glucose utilization, glucose is phosphorylated by GCK. Ligand-activated PXR represses expression of both GLUT2 and GCK. PXR activation also relocates GLUT2 from the plasma membrane to the cytosol. Together, these alterations reduce postprandial hepatic glucose uptake.

Figure 2

PXR–4β-hydroxycholesterol–LXR pathway as a regulator of cholesterol transporters and its putative role in vascular tone regulation. PXR activation by xenobiotics elevates circulating 4βHC, leading to the induction of cholesterol efflux transporters ABCA1 and ABCG1 and the repression of cholesterol influx transporter LOX-1. In addition to ABCA1 and ABCG1, inducible degrader of the LDL receptor (IDOL), another LXR target, is induced by 4βHC. The exact mechanism of LOX-1 repression is currently not known. The effects of 4βHC in vascular tone regulation are yet to be explored.