Hua Xia, Sun Di-Yang, Zhang Wen-Jie, Fu Jiang-Tao, Tong Jie, Sun Si-Jia, Zeng Fei-Yan, Ouyang Shen-Xi, Zhang Guo-Yan, Wang Shu-Na, Li Dong-Jie, Miao Chao-Yu, Wang Pei
Department of Pharmacology, School of Pharmacy, Second Military Medical University/Naval Medical University, Shanghai, China.
Department of Pharmacy, Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University, Shanghai, China.
Br J Pharmacol. 2021 May;178(10):2111-2130. doi: 10.1111/bph.15008. Epub 2020 Mar 24.
Non-alcoholic fatty liver disease (NAFLD) is a worldwide public health problem with no established pharmacological therapy. Here, we explored the potential benefit of P7C3-A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a NAFLD model, induced in mice by a high-fat diet (HFD).
C57BL/6J mice were given a HFD (42% fat content) for 16 weeks to induce NAFLD. P7C3-A20 (20 mg·kg ·day ) was given by gavage for 2 weeks. Indirect calorimetry, histological analysis, immunoblotting, immunohistochemistry, and biomedical examinations were performed. Gut microbiota were determined using a 16S ribosomal RNA sequencing analysis.
P7C3-A20 treatment reduced body weight gain/adiposity, improved insulin resistance, promoted energy expenditure (O consumption/CO production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro-inflammatory factors), decreased necroptosis/apoptosis (receptor-interacting protein kinase 3, cleaved caspase-3, and TUNEL), and alleviated liver fibrosis and injury. Mechanistically, P7C3-A20 stimulated FGF21 and FGF1 via activating liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB-regulated transcription coactivator 2 (CRTC2). In AMPKα2 knockout mice, the protection of P7C3-A20 against HFD-induced metabolism abnormalities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, was abolished. P7C3-A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions of Akkermansia, Lactobacillus, and Prevotellaceae, while reducing the proportions of Enterobacteriaceae, Escherichia, and Parasutterella.
P7C3-A20 increased levels of NAD+ and alleviated NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2-dependent manner and shaping gut microbiota.
This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
非酒精性脂肪性肝病（NAFLD）是一个全球性的公共卫生问题，目前尚无成熟的药物治疗方法。在此，我们探讨了P7C3 - A20（一种具有神经保护活性的新型氨丙基咔唑化合物）在高脂饮食（HFD）诱导的小鼠NAFLD模型中的潜在益处。
给C57BL/6J小鼠喂食高脂饮食（脂肪含量42%）16周以诱导NAFLD。通过灌胃给予P7C3 - A20（20 mg·kg·天），持续2周。进行间接测热法、组织学分析、免疫印迹、免疫组化和生物医学检查。使用16S核糖体RNA测序分析确定肠道微生物群。
P7C3 - A20治疗可减少体重增加/肥胖，改善胰岛素抵抗，促进能量消耗（氧气消耗/二氧化碳产生），抑制脂质氧化，抑制肝脏炎症（库普弗细胞数量和促炎因子），减少坏死性凋亡/凋亡（受体相互作用蛋白激酶3、裂解的半胱天冬酶 - 3和TUNEL），并减轻肝纤维化和损伤。机制上，P7C3 - A20通过激活肝激酶B1（LKB1）和AMP活化蛋白激酶（AMPK）刺激成纤维细胞生长因子21（FGF21）和FGF1，进而导致CREB调节的转录共激活因子（CRTC2）的核转位减少。在AMPKα2基因敲除小鼠中，P7C3 - A20对高脂饮食诱导的代谢异常和脂肪堆积的保护作用以及血液中FGF21和FGF1的升高被消除。P7C3 - A20增加了肠道微生物群的物种丰富度。此外，它提高了阿克曼氏菌、乳酸杆菌和普雷沃氏菌科的比例，同时降低了肠杆菌科、大肠杆菌和副萨特氏菌的比例。
P7C3 - A20通过以LKB1/AMPK/CRTC2依赖性方式刺激FGF21和FGF1并塑造肠道微生物群，提高NAD +水平并减轻NAFLD。
本文是关于细胞代谢与疾病的主题系列文章的一部分。若要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc。
