NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, Nottingham, UK.
Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
Mol Syst Biol. 2021 Oct;17(10):e10459. doi: 10.15252/msb.202110459.
Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.
非酒精性脂肪性肝病（NAFLD）是指肝脏中脂肪堆积过多。在动物实验和人体动力学研究中，我们发现联合代谢激活剂（CMAs）的给药促进脂肪氧化，减轻由此产生的氧化应激，激活线粒体，最终从肝脏中去除多余的脂肪。在这里，我们在一项安慰剂对照的 10 周研究中测试了 CMA 在 NAFLD 患者中的安全性和疗效。我们发现 CMA 可显著降低肝脂肪变性和天门冬氨酸氨基转移酶、丙氨酸氨基转移酶、尿酸和肌酐水平，而安慰剂组在调整体重减轻后这些变量无差异。通过整合临床数据、血浆代谢组学和炎症蛋白质组学以及口腔和肠道宏基因组数据，我们揭示了与 NAFLD 患者肝脂肪减少和炎症相关的潜在分子机制，并确定了参与宿主-微生物组相互作用的关键参与者。总之，我们表明 CMA 可用于开发 NAFLD 患者的药物治疗策略。
