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

Qi Qu, Yan Chen, Yu Wang, Weiche Wang, Shating Long, Heng-Ye Yang, Jianfeng Wu, Mengqi Li, Xiao Tian, Xiaoyan Wei, Yan-Hui Liu, Shengrong Xu, Jinye Xiong, Chunyan Yang, Zhenhua Wu, Xi Huang, Changchuan Xie, Yaying Wu, Zheni Xu, Cixiong Zhang, Baoding Zhang, Jin-Wei Feng, Junjie Chen, Yuanji Feng, Huapan Fang, Liyun Lin, Xie Zk, Beibei Sun, Huayu Tian, Yong Yu, Hai-Long Piao, Xiao-Song Xie, Xianming Deng, Chen-Song Zhang () and Sheng-Cai Lin ()
Additional contact information
Qi Qu: Xiamen University
Yan Chen: Xiamen University
Yu Wang: Xiamen University
Weiche Wang: Xiamen University
Shating Long: Xiamen University
Heng-Ye Yang: Xiamen University
Jianfeng Wu: Xiamen University
Mengqi Li: Xiamen University
Xiao Tian: Xiamen University
Xiaoyan Wei: Xiamen University
Yan-Hui Liu: Xiamen University
Shengrong Xu: Xiamen University
Jinye Xiong: Xiamen University
Chunyan Yang: Xiamen University
Zhenhua Wu: Xiamen University
Xi Huang: Xiamen University
Changchuan Xie: Xiamen University
Yaying Wu: Xiamen University
Zheni Xu: Xiamen University
Cixiong Zhang: Xiamen University
Baoding Zhang: Xiamen University
Jin-Wei Feng: Xiamen University
Junjie Chen: Xiamen University
Yuanji Feng: Xiamen University
Huapan Fang: Xiamen University
Liyun Lin: Xiamen University
Xie Zk: Xiamen University
Beibei Sun: Xiamen University
Huayu Tian: Xiamen University
Yong Yu: Xiamen University
Hai-Long Piao: Chinese Academy of Sciences
Xiao-Song Xie: University of Texas Southwestern Medical Center
Xianming Deng: Xiamen University
Chen-Song Zhang: Xiamen University
Sheng-Cai Lin: Xiamen University

Nature, 2025, vol. 643, issue 8070, 201-209

Abstract: 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 sirtuin 1 (SIRT1) identified TUB-like protein 3 (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.

Date: 2025
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DOI: 10.1038/s41586-024-08348-2

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