The Function of Xenobiotic Receptors in Metabolic Diseases

Abstract

Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobioticsensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases.However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs.

Adipocyte-Derived PXR Signaling Is Dispensable for Diet-Induced Obesity and Metabolic Disorders in Mice

“…As a key xenobiotic receptor, the functions of PXR in regulating xenobiotic metabolism have been extensively investigated by many groups and the role of PXR as a xenobiotic sensor has been established Kliewer et al, 2002;Zhou et al, 2009b). New evidence has suggested novel functions of PXR beyond xenobiotic metabolism, and several studies have also indicated that PXR may play an important role in obesity and metabolic disorders (Zhou, 2016;Zhang et al, 2023). However, the cell type-specific functions of PXR in obesity have not been investigated.…”

“…Recent studies from our laboratory and others revealed novel functions of PXR in cardiometabolic disease including obesity, diabetes and cardiovascular disease (CVD) beyond xenobiotic metabolism (Bhalla et al, 2004;Kodama et al, 2004;Kodama et al, 2007;de Haan et al, 2009;Zhou et al, 2009a;Cheng et al, 2012;He et al, 2013;Spruiell et al, 2014a;Spruiell et al, 2014b;Sui et al, 2015;Zhou, 2016;Helsley and Zhou, 2017;Gwag et al, 2019;Zhang et al, 2023). Several studies have also investigated the function of PXR in obesity and metabolic disorders.…”

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

“…PXR and CAR are transcription factors and have since been defined as master regulators of xenobiotic responses through their transcriptional regulation of drug-metabolizing enzymes and transporters, including CYPs (Poudel et al, 2022). Activation of PXR and CAR is also associated with the development of numerous metabolic diseases (Zhang et al, 2022). At a molecular level, when a drug, which can induce CYP expression, is taken up into a metabolic cell, it can serve as a ligand to bind to either PXR or CAR in its ligand binding domain.…”