Yang Hong, Mayneris-Perxachs Jordi, Boqué Noemí, Del Bas Josep M, Arola Lluís, Yuan Meng, Türkez Hasan, Uhlén Mathias, Borén Jan, Zhang Cheng, Mardinoglu Adil, Caimari Antoni
Science for Life Laboratory, KTH Royal Institute of Technology, SE-17165 Stockholm, Sweden.
Department of Diabetes, Endocrinology and Nutrition, Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Doctor Josep Trueta, 17190 Girona, Spain.
Biomedicines. 2021 Oct 11;9(10):1440. doi: 10.3390/biomedicines9101440.
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD.
尽管非酒精性脂肪性肝病（NAFLD）的患病率持续上升，但目前尚无针对该病症的有效获批治疗方法。我们之前在高脂饮食（HFD）喂养的小鼠中发现，补充包括烟酰胺核糖（NAD前体）以及强效谷胱甘肽前体丝氨酸和N-乙酰-L-半胱氨酸（NAC）的联合代谢激活剂（CMA），可通过促进线粒体中的脂肪氧化显著减轻脂肪肝。此后，在一项为期一天的概念验证人体补充研究中，我们观察到这种还包括L-肉碱酒石酸盐（LCT）的CMA可导致脂肪酸氧化增加和从头合成谷胱甘肽。然而，与补充CMA相关的潜在分子机制尚未完全阐明。在此，我们在仓鼠中证明，以两种剂量长期补充这种CMA（用甜菜碱替代丝氨酸）可显著降低肝脂肪变性。我们进一步生成了肝脏转录组学数据，并使用肝脏组织特异性的全基因组规模代谢模型整合了这些数据。我们系统地确定了补充CMA后的分子变化，发现它通过调节整体脂质、氨基酸、抗氧化剂和叶酸代谢来激活肝脏组织中的线粒体。我们的研究结果为基于这种CMA的治疗对NAFLD的有益作用提供了额外证据。
