Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Int J Mol Sci. 2022 Aug 16;23(16):9196. doi: 10.3390/ijms23169196.
The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the "multiple strikes" theory, the classic "two strikes" theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR's influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.
非酒精性脂肪性肝病（NAFLD）的全球患病率持续上升，但由于该病的发病机制复杂，目前仍缺乏有效的治疗方法。尽管最近的研究为“多次打击”理论提供了证据，但经典的“两次打击”理论尚未被推翻。因此，迫切需要确定 NAFLD 发病机制中的多个靶点，以开发诊断标志物和靶向治疗药物。自发现以来，雷帕霉素靶蛋白（mTOR）一直被认为是调节细胞生长和发育的网络的中心节点，与肝脏脂质代谢和其他过程密切相关。本文将探讨 mTOR 调节脂质代谢（SREBPs）、胰岛素抵抗（Foxo1、Lipin1）、氧化应激（PIG3、p53、JNK）、肠道微生物群（TLRs）、自噬、炎症、遗传多态性和表观遗传学在 NAFLD 中的作用机制。假设 mTOR 对 NAFLD 的具体影响可分为微观调节（mTOR 对 NAFLD 因素的影响机制）和宏观调节（各种影响因素之间的关系），以总结 mTOR 对 NAFLD 发展过程的影响，并从多个方面证明 mTOR 作为 NAFLD 影响因素的重要性。还总结了 mTOR 与其上游调节剂 Notch、Hedgehog 和 Hippo 之间的串扰对与 NAFLD 相关的肝细胞癌发生和发展的影响。希望该分析能够支持 NAFLD 诊断标志物和新治疗靶点的开发。
