Abstract
Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.
Highlights
Hypercholesterolemia, e.g., elevated low-density lipoprotein (LDL) cholesterol (LDL-C) and imbalance of LDLC and high-density lipoprotein cholesterol (HDL-C), is a central causative risk factor of atherosclerosis [1,2]
We showed that increased cholesterol synthesis due to pregnane X receptor (PXR) activation was caused by the induction of the Kandutsch–Russell pathway, as evidenced by increased plasma and hepatic markers of the pathway, lathosterol and zymostenol, and induced DHCR24, an enzyme that directs cholesterol synthesis to the Kandutsch–Russell pathway [30]
We have reported that rifampicin induces CYP3A4-mediated formation of 4β-hydroxycholesterol
Summary
Hypercholesterolemia, e.g., elevated LDL cholesterol (LDL-C) and imbalance of LDLC and high-density lipoprotein cholesterol (HDL-C), is a central causative risk factor of atherosclerosis [1,2]. It has been hypothesized that PXR activation may partly explain the adverse metabolic effects of environmental chemical exposure and drugs [12,13]. Exposure to drugs is usually well-controlled and both the exposure time and the dose are known For this reason, the effects of individual drugs on metabolic health are much better known than those of environmental chemicals, and this information could serve as a tool to understand the molecular mechanisms involved and subsequently help to predict the effects of other types of chemicals. We survey the current knowledge on the cholesterol-elevating effect of clinically used drugs and discuss a putative role of PXR in these effects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
