The Role of Xenobiotic Receptors on Hepatic Glycolipid Metabolism

Abstract

Background: PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) are termed as xenobiotic receptors, which are known as core factors in regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis and β-oxidation. Therefore, in this review, we are trying to summary recent advances to show how xenobiotic receptors regulate energy metabolism. Methods: A structured search of databases has been performed by using focused review topics. According to conceptual framework, the main idea of research literature was summarized and presented. Results: For introduction of each receptor, the general introduction and the critical functions in hepatic glucose and lipid metabolism have been included. Recent important studies have shown that CAR acts as a negative regulator of lipogenesis, gluconeogenesis and β -oxidation. PXR activation induces lipogenesis, inhibits gluconeogenesis and inhabits β-oxidation. Conclusion: In this review, the importance of xenobiotic receptors in hepatic glucose and lipid metabolism has been confirmed. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. However, further research is required to promote the clinical application of this new energy metabolism function of xenobiotic receptors.

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

“…Upon fasting, G6Pase and PEPCK1 genes are reactivated by the transcription factor forkhead box O1 (FoxO1) to initiate gluconeogenesis in the absence of insulin. Mechanistically, CAR can bind and repress FoxO1 [ 118 ], preventing it from interacting with the insulin response elements in insulin-like growth factor-binding protein (IGF-BP) 1, pyruvate carboxylase (PCX), fructose bisphosphatase 1 (FBP1), PEPCK1 and G6Pase upstream regions, and thus, suppressing the expression of these gluconeogenic genes [ 119 ]. CAR can compete with HNF4α for binding to the PEPCK promoter [ 99 ] or for metabolic coregulators, such as peroxisome proliferator-activated receptor γ coactivator-1 (PGC1)α or glucocorticoid receptor-interacting protein 1 (GRIP1) [ 110 , 120 ].…”

“…This may be caused by CAR-dependent repression of FoxA2 and HNF4α transcription factors. CAR modulates the expression of fatty acid synthase (FASN), acetyl-CoA carboxylase 1 (ACC1), and stearoyl-CoA desaturase 1 (SCD1) that control de novo fatty acid biosynthesis [ 119 ]. While the expression of FASN and ACC1 increased after CAR activation in wild-type mice, the expression of SCD1 and the sterol regulatory element-binding protein-1c (SREBP-1c) was significantly decreased, suggesting complexities in regulatory networks.…”

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

“…Therefore, a balance between PXR transcriptional activation and repression is needed, not only to maintain appropriate physiologic levels of endogenous chemicals but also to achieve optimal therapeutic efficacy with fewer drug‐induced toxicities. Because of its important role in regulating drug efficacy and drug toxicity, as well as its emerging roles in other physiologic and pathologic processes such as energy metabolism and metabolic diseases, infectious diseases, cancer, and inflammatory bowel disease (IBD), as briefly discussed in Sections to , PXR has become an attractive therapeutic target . However, PXR is notorious for promiscuously binding structurally diverse chemicals, including clinical drugs, environmental toxins, and endogenous metabolites, making it a challenging therapeutic target partly because of the perceived difficulty of studying its structure‐activity relationship .…”

“…The role of PXR in glucose metabolism has been reviewed recently . It has become evident that PXR is interconnected to impaired glucose tolerance, based on findings from human clinical studies involving drugs that activate hPXR, such as rifampicin (also known as rifampin), and from animal studies using rat models and pregnenolone 16α‐carbonitrile (PCN), which is an agonist of both rat PXR and mouse PXR (mPXR) .…”

“…The role of PXR in lipid metabolism has also been reviewed recently . PXR has a profound effect on the homeostasis of lipids, and its agonist‐induced activation causes hepatic steatosis, which is characterized by the repression of β‐oxidation and the induction of lipogenesis .…”