Abstract
Pregnane X receptor (PXR) is known to function as a xenobiotic sensor to regulate xenobiotic metabolism through selective transcription of genes responsible for maintaining physiological homeostasis. Here we report that the activation of PXR by pregnenolone 16α-carbonitrile (PCN) in AKR/J mice can prevent the development of high-fat diet-induced obesity and insulin resistance. The beneficial effects of PCN treatment are seen with reduced lipogenesis and gluconeogenesis in the liver, and lack of hepatic accumulation of lipid and lipid storage in the adipose tissues. RT-PCR analysis of genes involved in gluconeogenesis, lipid metabolism and energy homeostasis reveal that PCN treatment on high-fat diet-fed mice reduces expression in the liver of G6Pase, Pepck, Cyp7a1, Cd36, L-Fabp, Srebp, and Fas genes and slightly enhances expression of Cyp27a1 and Abca1 genes. RT-PCR analysis of genes involved in adipocyte differentiation and lipid metabolism in white adipose tissue show that PCN treatment reduces expression of Pparγ2, Acc1, Cd36, but increases expression of Cpt1b and Pparα genes in mice fed with high-fat diet. Similarly, PCN treatment of animals on high-fat diet increases expression in brown adipose tissue of Pparα, Hsl, Cpt1b, and Cd36 genes, but reduces expression of Acc1 and Scd-1 genes. PXR activation by PCN in high-fat diet fed mice also increases expression of genes involved in thermogenesis in brown adipose tissue including Dio2, Pgc-1α, Pgc-1β, Cidea, and Ucp-3. These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance.
Highlights
Pregnane X receptor (PXR; steroid and xenobiotic receptor or SXR) is a nuclear hormone receptor activated by xenobiotics as well as by diverse steroids and their metabolites [1,2,3]
For animals fed with high-fat diet, pregnenolone 16a-carbonitrile (PCN) treatment resulted in a significant decrease in growth rate as compared to those treated with DMSO
We demonstrate that activation of PXR by PCN prevented development of high-fat diet-induced obesity and relieved obesity-related insulin resistance and hepatic lipid accumulation (Figures 1, 3, 4)
Summary
Pregnane X receptor (PXR; steroid and xenobiotic receptor or SXR) is a nuclear hormone receptor activated by xenobiotics as well as by diverse steroids and their metabolites [1,2,3]. PXR is known to induce, upon ligand binding, the expression of genes coding for phase I (Cyp3a11, CYP3A4, Cyp2b10) and phase II (Sult2a1, UDP-glucuronosyltransferase and GST) enzymes and drug transporters (MDR1) [4]. A good example of PXR-mediated regulation is transcription of CYP3A4 gene encoding an enzyme responsible for the metabolism of more than 50% of clinical drugs [5]. A number of clinical observations using PXR activators have linked PXR to lipid metabolism and energy homeostasis. Treating children with antiepileptic drugs carbamazipine and phenobarbital for an extended time, could activate PXR and increase cholesterol levels [7]. PXR modulated sterol regulatory element binding protein 1 (SREBP-1) by inducing Insig expression, resulting in decreased levels of active SREBP-1 and reduced triglyceride synthesis [9]. Additional studies are needed to resolve the seemingly contradictory effects of PXR activation in lipid homeostasis, the results from these studies firmly establish the role of PXR in regulating lipid and energy homeostasis at multiple levels
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