厦门大学林圣彩等研究人员合作发现，石胆酸通过结合TULP3激活sirtuin和AMPK来减缓衰老过程。2024年12月18日，《自然》杂志在线发表了这项成果。

研究人员表示，LCA在哺乳动物进行热量限制时积累，能够激活AMPK从而减缓衰老。然而，LCA如何激活AMPK并引发这些生物学效应的分子机制尚不明确。

研究人员发现石胆酸（LCA）增强去sirtuin的活性，去乙酰化并抑制液泡H⁺-ATP酶（v-ATP酶），进而通过溶酶体葡萄糖感应通路激活AMP-激活蛋白激酶（AMPK）。通过蛋白质组学分析与去乙酰化酶1（SIRT1）共免疫沉淀的蛋白质，鉴定出TUB样蛋白3（TULP3），一个与sirtuin相互作用的蛋白，作为LCA受体。

具体而言，LCA与TULP3结合，通过变构激活sirtuin，后者去乙酰化v-ATP酶的V1E1亚单位的K52、K99和K191位点。肌肉特异性表达V1E1突变体（3KR），该突变体模拟去乙酰化状态，能够强烈激活AMPK，并在衰老小鼠中恢复肌肉活力。在线虫和果蝇中，LCA依赖于TULP3同源物tub-1和ktub分别激活AMPK，延长寿命和健康寿命。该研究表明，LCA通过激活TULP3–sirtuin–v-ATP酶–AMPK通路，复制了热量限制的益处。

附：英文原文

Title: Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing

Author: Qu, Qi, Chen, Yan, Wang, Yu, Wang, Weiche, Long, Shating, Yang, Heng-Ye, Wu, Jianfeng, Li, Mengqi, Tian, Xiao, Wei, Xiaoyan, Liu, Yan-Hui, Xu, Shengrong, Xiong, Jinye, Yang, Chunyan, Wu, Zhenhua, Huang, Xi, Xie, Changchuan, Wu, Yaying, Xu, Zheni, Zhang, Cixiong, Zhang, Baoding, Feng, Jin-Wei, Chen, Junjie, Feng, Yuanji, Fang, Huapan, Lin, Liyun, Xie, ZK, Sun, Beibei, Tian, Huayu, Yu, Yong, Piao, Hai-Long, Xie, Xiao-Song, Deng, Xianming, Zhang, Chen-Song, Lin, Sheng-Cai

Issue&Volume: 2024-12-18

Abstract: Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins that co-immunoprecipitated with sirtuin1 (SIRT1) identified TUB-like protein3 (TULP3), a sirtuin-interacting protein2, as a LCA receptor. In detail, LCA-bound TULP3 allosterically activates sirtuins, which then deacetylate the V1E1 subunit of v-ATPase on residues K52, K99 and K191. Muscle-specific expression of a V1E1 mutant (3KR), which mimics the deacetylated state, strongly activates AMPK and rejuvenates muscles in aged mice. In nematodes and flies, LCA depends on the TULP3 homologues tub-1 and ktub, respectively, to activate AMPK and extend lifespan and healthspan. Our study demonstrates that activation of the TULP3–sirtuin–v-ATPase–AMPK pathway by LCA reproduces the benefits of calorie restriction.

DOI: 10.1038/s41586-024-08348-2

Source: https://www.nature.com/articles/s41586-024-08348-2