datasheet1_Epigallocatechin Gallate During Dietary Restriction — Potential Mechanisms of Enhanced Liver Injury.pdf

Green tea extract (GTE) is popular in weight loss, and epigallocatechin gallate (EGCG) is considered as the main active component. However, GTE is the primary cause of herbal and dietary supplement-induced liver injury in the United States. Whether there is a greater risk of liver injury when EGCG is consumed during dieting for weight loss has not been previously reported. This study found for the first time that EGCG could induce enhanced lipid metabolism pathways, suggesting that EGCG had the so-called “fat burning” effect, although EGCG did not cause liver injury at doses of 400 or 800 mg/kg in normal mice. Intriguingly, we found that EGCG caused dose-dependent hepatotoxicity on mice under dietary restriction, suggesting the potential combination effects of dietary restriction and EGCG. The combination effect between EGCG and dietary restriction led to overactivation of linoleic acid and arachidonic acid oxidation pathways, significantly increasing the accumulation of pro-inflammatory lipid metabolites and thus mediating liver injury. We also found that the disruption of Lands’ cycle and sphingomyelin-ceramides cycle and the high expression of taurine-conjugated bile acids were important metabolomic characteristics in EGCG-induced liver injury under dietary restriction. This original discovery suggests that people should not go on a diet while consuming EGCG for weight loss; otherwise the risk of liver injury will be significantly increased. This discovery provides new evidence for understanding the “drug-host” interaction hypothesis of drug hepatotoxicity and provides experimental reference for clinical safe use of green tea-related dietary supplements.

绿茶提取物（GTE）在减肥领域广受欢迎，其中表没食子儿茶素没食子酸酯（EGCG）被视为其主要活性成分。然而，GTE是美国草药和膳食补充剂引起的肝脏损伤的主要原因。在减肥期间摄入EGCG是否会导致更大的肝脏损伤风险，此前尚未有报道。本研究首次发现，EGCG可诱导增强的脂质代谢途径，表明EGCG具有所谓的“燃脂”效应，尽管在400或800 mg/kg的剂量下EGCG并未导致正常小鼠的肝脏损伤。令人好奇的是，我们发现EGCG在饮食限制的小鼠中引起剂量依赖性的肝毒性，暗示了饮食限制与EGCG的潜在联合效应。EGCG与饮食限制之间的联合效应导致亚油酸和花生四烯酸氧化途径过度活化，显著增加了促炎脂质代谢产物的积累，从而介导肝脏损伤。我们还发现，Lands循环和鞘磷脂-鞘氨醇循环的破坏以及牛磺酸结合胆汁酸的高表达是EGCG在饮食限制下引起肝脏损伤的重要代谢组学特征。这一原创发现表明，人们在减肥期间不应同时摄入EGCG；否则，肝脏损伤的风险将显著增加。这一发现为理解药物-宿主相互作用假说提供了新的证据，并为绿色茶相关膳食补充剂的临床安全使用提供了实验参考。