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.
Highlights
Metabolic syndrome (MetS) is a cluster of risk factors that increases the risk of coronary heart disease, type 2 diabetes, and stroke [1,2]
The results reviewed above indicate that Pregnane X receptor (PXR) activation and especially elevated 4βHC levels could be beneficial factors in the regulation of HDL metabolism
There is robust evidence in humans that glucose tolerance is impaired and that blood pressure is elevated by PXR activation
Summary
Metabolic syndrome (MetS) is a cluster of risk factors that increases the risk of coronary heart disease, type 2 diabetes, and stroke [1,2]. The components of MetS include abdominal obesity, hyperglycemia, high blood pressure, low HDL cholesterol, and elevated triglycerides. Exposure to environmental pollutants has been suggested to be an additional risk factor for the development of MetS [6,7]. These metabolism-disrupting or endocrine-disrupting chemicals (EDCs) are especially linked to the incidence of type 2 diabetes and its preceding phenomena, namely insulin resistance and prediabetes [8,9]. There are links between exposure to EDCs and the other components of MetS, i.e., hypertension, low HDL cholesterol (HDL-C), and elevated triglycerides [7]. We concentrate on the effects of PXR on MetS and discuss the possibility that, due to its roles as a xenosensor and a regulator of glucose and lipid metabolism as well as blood pressure [13,14], PXR activation could contribute to the development of MetS
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