Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, China.
National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Changsha, Hunan 410128, China.
Food Funct. 2023 Jul 3;14(13):6172-6186. doi: 10.1039/d3fo01001e.
Extreme heat caused by global warming accelerated the frequency of heat stress (HS). Proteotoxic stress induced by the aggregation of misfolded proteins and metabolic stress triggered by alterations in the metabolism were observed during HS. The activation of heat shock factor 1 (Hsf1) and its interaction with adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) are critical in addressing proteotoxicity and metabolic stress in heat-stressed organisms. Previous studies have shown that L-theanine (LTA) can regulate nutrient metabolism through the AMPK pathway and can alleviate HS. Therefore, we hypothesize that LTA may help in restoring homeostasis by regulating nutrient metabolism under HS. Here, we investigated the effects of LTA on nutrient metabolism in heat-stressed rats and characterized the underlying mechanisms using RNA sequencing and metabonomics. The results showed that LTA alleviated HS-induced liver damage, promoted body weight gain, decreased serum cortisol and enhanced the total protein content. Besides, it regulated the expression of genes related to carbohydrate, lipid and amino acid metabolism and altered metabolite levels. Moreover, LTA inhibited the expression of Hsf1 and heat shock protein 70 (Hsp70), promoted AMPK phosphorylation and the expression of glucose-6-phosphatase catalytic subunit 1 (), and inhibited the phosphorylation of acetyl-CoA carboxylase 1 (ACC1) in heat-stressed rats. Mechanistically, LTA alleviated HS-induced proteotoxic stress by acting on Hsf1/Hsp70; simultaneously, it promoted AMPK phosphorylation by suppressing Hsf1 expression, which in turn inhibited fatty acid synthesis and hepatic gluconeogenesis, thus alleviating HS-induced metabolic stress. These results suggest that LTA regulates nutrient metabolism through Hsf1/AMPK and alleviates HS-induced proteotoxicity Hsf1/Hsp70.
全球变暖导致的极端高温加速了热应激 (HS) 的频率。在高温下，观察到错误折叠蛋白质聚集引起的蛋白质毒性应激和代谢改变引起的代谢应激。热休克因子 1 (Hsf1) 的激活及其与腺苷 5'-单磷酸 (AMP)-激活的蛋白激酶 (AMPK) 的相互作用对于解决热应激生物中的蛋白质毒性和代谢应激至关重要。先前的研究表明，L-茶氨酸 (LTA) 可以通过 AMPK 途径调节营养代谢，并可以减轻 HS。因此，我们假设 LTA 可以通过调节营养代谢来帮助恢复高温下的体内平衡。在这里，我们研究了 LTA 对热应激大鼠营养代谢的影响，并通过 RNA 测序和代谢组学对其潜在机制进行了表征。结果表明，LTA 减轻了 HS 引起的肝损伤，促进了体重增加，降低了血清皮质醇水平，并增强了总蛋白含量。此外，它调节了与碳水化合物、脂质和氨基酸代谢相关的基因的表达，并改变了代谢物水平。此外，LTA 抑制了 Hsf1 和热休克蛋白 70 (Hsp70) 的表达，促进了 AMPK 磷酸化和葡萄糖-6-磷酸酶催化亚基 1 () 的表达，并抑制了热应激大鼠中乙酰辅酶 A 羧化酶 1 (ACC1) 的磷酸化。从机制上讲，LTA 通过作用于 Hsf1/Hsp70 减轻了 HS 引起的蛋白质毒性应激；同时，它通过抑制 Hsf1 表达促进了 AMPK 的磷酸化，从而抑制了脂肪酸合成和肝糖异生，从而减轻了 HS 引起的代谢应激。这些结果表明，LTA 通过 Hsf1/AMPK 调节营养代谢，并通过 Hsf1/Hsp70 减轻 HS 引起的蛋白质毒性应激。
