Nutritional status modifies pregnane X receptor regulated transcriptome

Abstract

Pregnane X receptor (PXR) regulates glucose and lipid metabolism, but little is known of the nutritional regulation of PXR function. We investigated the genome wide effects of the nutritional status on the PXR mediated gene regulation in the liver. Mice were treated with a PXR ligand pregnenolone 16α-carbonitrile (PCN) for 4 days and subsequently either fasted for 5 hours or after 4-hour fast treated with intragastric glucose 1 hour before sample collection. Gene expression microarray study indicated that PCN both induced and repressed much higher number of genes in the glucose fed mice and the induction of multiple well-established PXR target genes was potentiated by glucose. A subset of genes, including bile acid synthesis gene Cyp8b1, responded in an opposite direction during fasting and after glucose feeding. PXR knockout abolished these effects. In agreement with the Cyp8b1 regulation, PCN also modified the bile acid composition in the glucose fed mice. Contribution of glucose, insulin and glucagon on the observed nutritional effects was investigated in primary hepatocytes. However, only mild impact on PXR function was observed. These results show that nutritional status modifies the PXR regulated transcriptome both qualitatively and quantitatively and reveal a complex crosstalk between PXR and energy homeostasis.

Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2‐mediated mechanism

“…Feeding may affect metabolic responses and a recent study utilizing metabolomics approach similar to this study reported the effect of glucose feeding (Wang et al, 2019). Moreover, we have reported the modifying effect of glucose feeding on PXR function in mouse liver (Hassani‐Nezhad‐Gashti et al, 2019). To analyse dynamics of the lipidome during glucose challenge in response to rifampicin, we utilized a third clinical study, Rifa‐2, with oral glucose tolerance test (oral glucose tolerance test) in 12 healthy volunteers before and after 1‐week rifampicin dosing.…”

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

“…Although significant levels of several K vitamers (particularly MK-4) were found in tissues, like mammalian thyroid and adrenal gland [ 9 , 16 ], and ggcx , vkorc1 and vkorc1l1 were reported to be expressed in the adrenal gland of male and female mice [ 92 ], little is known regarding how VK might affect thyroid and adrenal hormones signaling. While PXR-regulated transcriptome is dependent on the nutritional status, affecting thyroid hormone metabolism II in mice [ 156 ], several studies have shown that PXR plays an important role in adrenal steroid hormone homeostasis. Activation of PXR markedly increases plasma concentrations of corticosterone and aldosterone, the primary glucocorticoid and mineralocorticoid in rodents, being associated to the activation of adrenal steroidogenic enzymes, including CYP11A1, CYP11B1, CYP11B2, and HSD3B2 [ 157 ].…”

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

“…As one example, exposure to statins is a known risk factor for type 2 diabetes (e.g., [ 234 ]). Although statins can activate CAR modestly [ 235 ], they affect PXR more strongly [ 236 ]. Other mechanisms underlying the statin-elicited increase in blood glucose levels likely exist [ 237 ].…”