Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature.
Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature.
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DOI：
10.1016/j.bcp.2021.114698
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发表时间：
2021-11
影响因子：
5.8
通讯作者：
Gyamfi, Maxwell A.
中科院分区：
文献类型：
--
作者：
Kim, Sarah;Choi, Sora;Dutta, Moumita;Asubonteng, Jeffrey O.;Polunas, Marianne;Goedken, Michael;Gonzalez, Frank J.;Cui, Julia Yue;Gyamfi, Maxwell A.
非酒精性脂肪性肝病（NAFLD）是目前流行的肥胖和糖尿病导致的最常见的慢性肝病。PXR是一种异生物质敏感的核受体，已知其反式激活参与药物代谢和转运的肝脏基因，最近还参与能量代谢。肠道微生物群可以调节宿主异生物质的生物转化，并有助于肥胖的发展。虽然男性比更年期前的女性患NAFLD的风险更高，但其机制仍不清楚。我们假设PXR的存在通过以性别特异性的方式改变胃肠道轴而促进肥胖。雄性和雌性C57 BL/6（野生型/WT）和PXR敲除（PXR-KO）小鼠喂食对照或高脂饮食（HFD）16周。进行血清参数、肝组织病理学、转录组学分析、16 S-rDNA测序和胆汁酸（BA）代谢组学。PXR增强了HFD诱导的体重增加、肝脏脂肪变性和炎症，尤其是在男性中，伴随着与微生物反应、炎症、氧化应激和癌症有关的肝脏基因的PXR依赖性上调;肠厚壁菌门/拟杆菌属比率的PXR依赖性增加（肥胖的标志）和促炎性乳酸杆菌，以及抗肥胖的Allobaculum和抗炎的Biobaculum的减少，肝脏中有益BA的PXR依赖性减少。女性对NAFLD的抗性可以通过促炎细菌（活泼瘤胃球菌和消化球菌科）的PXR依赖性减少来解释。总之，PXR加剧了肝脏脂肪变性和炎症，伴有肥胖和炎症倾向的肠道微生物组特征，表明肠道微生物组可能有助于PXR介导的NAFLD恶化。
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease due to the current epidemics of obesity and diabetes. The pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor known for transactivating liver genes involved in drug metabolism and transport, and more recently implicated in energy metabolism. The gut microbiota can modulate the host xenobiotic biotransformation and contribute to the development of obesity. While the male sex confers a higher risk for NAFLD than women before menopause, the mechanism remains unknown. We hypothesized that the presence of PXR promotes obesity by modifying the gutliver axis in a sex-specific manner. Male and female C57BL/6 (wild-type/WT) and PXR-knockout (PXR-KO) mice were fed control or high-fat diet (HFD) for 16-weeks. Serum parameters, liver histopathology, transcriptomic profiling, 16S-rDNA sequencing, and bile acid (BA) metabolomics were performed. PXR enhanced HFD-induced weight gain, hepatic steatosis and inflammation especially in males, accompanied by PXR-dependent up-regulation in hepatic genes involved in microbial response, inflammation, oxidative stress, and cancer; PXR-dependent increase in intestinal Firmicutes/Bacteroides ratio (hallmark of obesity) and the pro-inflammatory Lactobacillus, as well as a decrease in the anti-obese Allobaculum and the anti-inflammatory Bifidobacterum, with a PXR-dependent reduction of beneficial BAs in liver. The resistance to NAFLD in females may be explained by PXR-dependent decrease in pro-inflammatory bacteria (Ruminococcus gnavus and Peptococcaceae). In conclusion, PXR exacerbates hepatic steatosis and inflammation accompanied by obesity- and inflammationprone gut microbiome signature, suggesting that gut microbiome may contribute to PXR-mediated exacerbation of NAFLD.
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影响因子：
7.9
作者：
Chhiber, Nirlep;Kaur, Tanzeer;Singla, Surinder
通讯作者：
Singla, Surinder
影响因子：
7.7
作者：
He J;Gao J;Xu M;Ren S;Stefanovic-Racic M;O'Doherty RM;Xie W
通讯作者：
Xie W
DOI：
10.1016/j.bbagrm.2016.04.010
发表时间：
2016-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cui JY;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
4.8
作者：
Gao, Jie;He, Jinhan;Xie, Wen
通讯作者：
Xie, Wen
影响因子：
3.8
作者：
Cheng, Sunny Lihua;Li, Xueshu;Cui, Julia Yue
通讯作者：
Cui, Julia Yue