氨基酸是蛋白质的基本组成单位和重要的代谢信号分子,在糖脂代谢调控中发挥关键作用。研究表明,支链氨基酸(BCAAs)、芳香族氨基酸和含硫氨基酸的代谢紊乱与非酒精性脂肪肝(NAFLD)的发生发展密切相关。BCAAs通过激活mTOR信号通路,诱导氧化应激和线粒体功能障碍,促进胰岛素抵抗和肝脏脂质沉积。此外,亮氨酸缺乏可通过氨基酸感应器GCN2通路增强胰岛素敏感性,减少肝脏葡萄糖生成;而蛋氨酸缺乏则通过FGF21信号调控脂质代谢。临床研究发现,血清BCAAs水平与脂肪肝严重程度显著相关,提示其作为潜在生物标志物的价值。尽管靶向氨基酸代谢的干预策略,例如BCAA限制饮食、支链α-酮酸脱氢酶激酶(BCKDK)抑制剂在改善肝脏代谢方面展现出良好前景,但mTORC1抑制剂等治疗手段的代谢副作用提示氨基酸感知网络的复杂性。临床主要挑战包括:氨基酸代谢网络的动态平衡调控、干预措施的双重性验证,以及个体化治疗反应差异的预测等。未来研究需结合多组学技术,阐明氨基酸感知信号通路的组织特异性机制,开发基于代谢分型的个体化治疗方案,为NAFLD的精准防治提供新思路。
Abstract
Amino acids, as the basic building blocks of proteins and important metabolic signalling molecules, play a key role in the regulation of glycolipid metabolism.Studies have shown that metabolic disorders of branched-chain amino acids (BCAAs), aromatic amino acids and sulphur-containing amino acids are closely related to the development of non-alcoholic fatty liver disease (NAFLD).BCAAs induce oxidative stress and mitochondrial dysfunction through activation of the mTOR signalling pathway, which promotes insulin resistance and hepatic lipid deposition.In addition, leucine deficiency enhances insulin sensitivity and reduces hepatic glucose production through the GCN2 pathway, while methionine deficiency regulates lipid metabolism through FGF21 signalling.Clinical studies have found that serum BCAAs levels significantly correlate with fatty liver severity, suggesting their value as potential biomarkers.Although intervention strategies targeting amino acid metabolism, including BCAA-restricted diets, Branched-Chain α-Ketoacid Dehydrogenase Kinase (BCKDK) inhibitors, have shown promising results in improving hepatic metabolism, the metabolic side effects of treatments such as mTORC1 inhibitors suggest the complexity of the amino acid perception network.Current challenges include the regulation of the dynamic balance of amino acid metabolic networks, the long-term safety validation of interventions, and the prediction of differences in response to individualised treatments.Future studies need to incorporate multi-omics techniques to elucidate the tissue-specific mechanisms of amino acid sensing signalling pathways, develop individualised treatment plans based on metabolic typing, so as to provide new ideas for the precise prevention and treatment of NAFLD.
关键词
氨基酸 /
糖脂代谢 /
非酒精性脂肪肝
Key words
amino acids /
glycolipid metabolism /
non-alcoholic fatty liver disease
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基金
国家重点研发计划(2021YFC2701900, 2021YFC2701903)
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