Pregnane X receptor (PXR) deficiency improves high fat diet‐induced obesity via induction of fibroblast growth factor 15 (FGF15) expression
Pregnane X receptor (PXR) deficiency improves high fat diet‐induced obesity via induction of fibroblast growth factor 15 (FGF15) expression
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妊娠素X受体（PXR）缺乏通过诱导成纤维细胞生长因子15 （FGF15）表达改善高脂肪饮食诱导的肥胖
DOI：
10.1016/j.bcp.2017.07.019
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发表时间：
2017-10
影响因子：
5.8
通讯作者：
Li-yang Zhao;Jia‐Yi Xu;Zhe Shi;Neal A Englert;Shu-Yun Zhang
中科院分区：
文献类型：
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作者：
Li-yang Zhao;Jia‐Yi Xu;Zhe Shi;Neal A Englert;Shu-Yun Zhang
肥胖已成为一个重要的全球性健康问题，是多种代谢性疾病的高危因素。成纤维细胞生长因子（FGF）15在代谢调节中起重要作用。异生物素敏感核受体PXR/NR 1 I2和组成型雄烷受体CAR/NR 1 I3在异生物素解毒和代谢中发挥重要作用，并参与能量代谢的调节。然而，PXR和CAR对FGF 15的调节作用尚不清楚。在此，我们发现，与喂食高脂饮食（HFD）的野生型小鼠相比，喂食高脂饮食（HFD）的PXR敲除（KO）小鼠的体重、肝脏甘油三酯水平、肝脏脂肪变性以及胆固醇7α-羟化酶（CYP 7A 1）和固醇12α-羟化酶（CYP 8B 1）（胆汁酸经典合成途径中的关键酶）的肝脏mRNA表达水平显著降低。有趣的是，与HFD喂养的野生型小鼠相比，HFD喂养的PXR KO小鼠的肠道FGF 15表达水平显著升高。此外，当喂食对照饮食或HFD时，PXR KO小鼠的血清总胆汁酸水平显著低于野生型小鼠。与喂食HFD的野生型小鼠相比，喂食HFD的PXR KO小鼠粪便中的总脂质显著增加。然而，在HFD喂养的CAR KO小鼠中未发现这些变化。这些结果表明，PXR缺乏通过诱导FGF 15表达改善HFD诱导的肥胖，导致胆汁酸合成的抑制和脂质吸收、肝脂质积累和肝甘油三酯水平的降低。我们的研究结果表明，PXR可能负调控FGF 15的表达，并代表了一个潜在的治疗代谢紊乱，如肥胖症的治疗靶点。
Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown. Here, we found that body weight, hepatic triglyceride levels, liver steatosis, and hepatic mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), the key enzymes in the bile acid classical synthesis pathway, were significantly decreased in high fat diet (HFD)-fed PXR knockout (KO) mice compared to HFD-fed wild-type mice. Interestingly, intestinal FGF15 expression levels were significantly elevated in HFD-fed PXR KO mice compared with HFD-fed wild-type mice. Additionally, serum total bile acid levels were significantly decreased in PXR KO mice than those in wild-type mice when fed a control diet or HFD. Total lipids in feces were significantly increased in HFD-fed PXR KO mice compared to HFD-fed wild-type mice. However, these alterations were not found in HFD-fed CAR KO mice. These results indicate that PXR deficiency improves HFD-induced obesity via induction of FGF15 expression, resulting in suppression of bile acid synthesis and reduction of lipid absorption, hepatic lipid accumulation and liver triglyceride levels. Our findings suggest that PXR may negatively regulate FGF15 expression and represent a potential therapeutic target for the treatment for metabolic disorders such as obesity.