School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing China.
Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Hepatology. 2023 Dec 1;78(6):1828-1842. doi: 10.1097/HEP.0000000000000314. Epub 2023 Feb 22.
SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism.
In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα.
Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.
SLC25A47 最初被鉴定为一种线粒体 HCC 下调的载体蛋白，但它的生理功能和转运底物尚不清楚。我们旨在研究 SLC25A47 在肝代谢中的生理作用。
在使用二甲双胍处理肝细胞的过程中，我们发现二甲双胍可以转录激活 Slc25a47 的表达，这是 AMP 激活蛋白激酶α（AMPKα）磷酸化所必需的。Slc25a47 缺陷型小鼠肝脏脂质含量、甘油三酯和胆固醇水平增加，我们发现 Slc25a47 缺陷抑制了 AMPKα 的磷酸化，导致核 SREBPs 的积累增加，脂肪酸和胆固醇生物合成活性增强。相反，当 Slc25a47 在小鼠肝脏中过表达时，AMPKα 被激活，导致脂肪生成受到抑制。此外，我们使用二乙基亚硝胺诱导的小鼠 HCC 模型发现，Slc25a47 的缺失通过激活哺乳动物雷帕霉素靶蛋白级联反应促进 HCC 肿瘤的发生和发展。通过对 SLC25A47 进行同源建模和人代谢组数据库的虚拟筛选，我们证明 NAD+是 SLC25A47 的内源性底物，Slc25a47 缺陷型小鼠中 NAD+依赖的 Sirtuin 3 活性下降，随后 AMPKα失活。
我们的研究结果表明，SLC25A47 是一种肝细胞特异性线粒体 NAD+转运体，是二甲双胍的药理学靶点之一，通过 AMPKα调节脂质稳态，可能成为治疗非酒精性脂肪性肝病和 HCC 的潜在药物靶点。
