Deciphering the roles of the constitutive androstane receptor in energy metabolism

Abstract

The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

NTP Technical Report on the Toxicity Studies of Perfluoroalkyl Sulfonates (Perfluorobutane Sulfonic Acid, Perfluorohexane Sulfonate Potassium Salt, and Perfluorooctane Sulfonic Acid) Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

“…Studies have shown that administration of PPARα agonists, including PFAS, to rats results in lowered circulating triglyceride and cholesterol concentrations 47; 114-117 . CAR is also an important regulator of cholesterol homeostasis and its activation may also be related to the observed lipid alterations 118 . In addition, thyroid hormone triiodothyronine (T3) directly influences activities of critical enzymes in lipolytic pathways, and hypothyroidism in rats results in decreased blood triglyceride concentrations 119 .…”

NTP Technical Report on the Toxicity Studies of Perfluoroalkyl Carboxylates (Perfluorohexanoic Acid, Perfluorooctanoic Acid, Perfluorononanoic Acid, and Perfluorodecanoic Acid) Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

“…Studies have shown that administration of PPARα agonists to rats, including carboxylated PFAS, results in lowered circulating triglyceride and cholesterol concentrations 44; 141; 142 . CAR is also an important regulator of cholesterol homeostasis, and its activation may also be related to the observed lipid alterations 143 . In addition, thyroid hormone triiodothyronine (T3) directly influences activities of critical enzymes in lipolytic pathways, and hypothyroidism in rats results in decreased blood triglyceride concentrations 144 .…”

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome

“…Chronic exposure to rifaximin causes hepatic steatosis in PXR-humanized mice (Cheng et al, 2012); PXR-humanized mice fed a high-fat diet gain more body weight, exhibit hyperinsulinemia, and impaired glucose tolerance (Spruiell et al, 2014); whereas PXR depletion alleviates diet-induced and genetic obesity as well as insulin resistance in mice (He et al, 2013). Conversely, CAR has been found to be an anti-obesity sensor that regulates glucose and lipid metabolism, and improves insulin sensitivity in mice (Gao et al, 2009; Yan et al, 2015). In human hepatocytes, activation of CAR inhibits gluconeogenesis without suppressing fatty acid synthesis (Lynch et al, 2014).…”