Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Mol Metab. 2023 Oct;76:101779. doi: 10.1016/j.molmet.2023.101779. Epub 2023 Jul 17.
Both obesity and exposure to chemicals may induce non-alcoholic fatty liver disease (NAFLD). Pregnane X Receptor (PXR) is a central target of metabolism disrupting chemicals and disturbs hepatic glucose and lipid metabolism. We hypothesized that the metabolic consequences of PXR activation may be modified by existing obesity and associated metabolic dysfunction.
Wildtype and PXR knockout male mice were fed high-fat diet to induce obesity and metabolic dysfunction. PXR was activated with pregnenolone-16α-carbonitrile. Glucose metabolism, hepatosteatosis, insulin signaling, glucose uptake, liver glycogen, plasma and liver metabolomics, and liver, white adipose tissue, and muscle transcriptomics were investigated.
PXR activation aggravated obesity-induced liver steatosis by promoting lipogenesis and inhibiting fatty acid disposal. Accordingly, hepatic insulin sensitivity was impaired and circulating alanine aminotransferase level increased. Lipid synthesis was facilitated by increased liver glucose uptake and utilization of glycogen reserves resulting in dissociation of hepatosteatosis and hepatic insulin resistance from the systemic glucose tolerance and insulin sensitivity. Furthermore, glucagon-induced hepatic glucose production was impaired. PXR deficiency did not protect from the metabolic manifestations of obesity, but the liver transcriptomics and metabolomics profiling suggest diminished activation of inflammation and less prominent changes in the overall metabolite profile.
Obesity and PXR activation by chemical exposure have a synergistic effect on NAFLD development. To support liver fat accumulation the PXR activation reorganizes glucose metabolism that seemingly improves systemic glucose metabolism. This implies that obese individuals, already predisposed to metabolic diseases, may be more susceptible to harmful metabolic effects of PXR-activating drugs and environmental chemicals.
肥胖和接触化学物质都可能导致非酒精性脂肪性肝病（NAFLD）。孕烷 X 受体（PXR）是代谢干扰化学物质的核心靶标，可扰乱肝脏葡萄糖和脂质代谢。我们假设 PXR 激活的代谢后果可能会受到现有肥胖和相关代谢功能障碍的影响。
将野生型和 PXR 敲除雄性小鼠用高脂肪饮食喂养以诱导肥胖和代谢功能障碍。用孕烯醇酮-16α-腈激活 PXR。研究了葡萄糖代谢、肝脂肪变性、胰岛素信号、葡萄糖摄取、肝糖原、血浆和肝代谢组学以及肝、白色脂肪组织和肌肉转录组学。
PXR 激活通过促进脂肪生成和抑制脂肪酸处置，加剧了肥胖引起的肝脂肪变性。因此，肝胰岛素敏感性受损，循环丙氨酸氨基转移酶水平升高。通过增加肝葡萄糖摄取和利用糖原储备来促进脂质合成，导致肝脂肪变性和肝胰岛素抵抗与全身葡萄糖耐量和胰岛素敏感性分离。此外，胰高血糖素诱导的肝葡萄糖生成受损。PXR 缺失不能保护免受肥胖的代谢表现，但肝脏转录组学和代谢组学分析表明，炎症的激活程度降低，整体代谢物谱的变化不那么明显。
肥胖和化学物质暴露激活 PXR 对 NAFLD 的发展有协同作用。为了支持肝脂肪堆积，PXR 激活重新组织葡萄糖代谢，这似乎改善了全身葡萄糖代谢。这意味着已经容易发生代谢疾病的肥胖个体可能更容易受到 PXR 激活药物和环境化学物质的有害代谢影响。
