Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing
Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing<sup>1</sup>. 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<sup>+</sup>-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 protein<sup>2</sup>, 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.
Authors
- Chunyan Yang (ORCID: https://orcid.org/0000-0003-1790-3647)
- Xi Huang (ORCID: https://orcid.org/0000-0002-1898-6918)
- Changchuan Xie (ORCID: https://orcid.org/0000-0002-1078-0464)
- Jinye Xiong
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Shating Long
- Sheng‐Cai Lin (ORCID: https://orcid.org/0000-0003-1993-8376)
- Jianfeng Wu (ORCID: https://orcid.org/0000-0002-9770-5538)
- Huapan Fang (ORCID: https://orcid.org/0000-0003-4364-2196)
- Hai‐long Piao (ORCID: https://orcid.org/0000-0001-7451-0386)
- Xiao‐Song Xie (ORCID: https://orcid.org/0000-0001-7013-4571)
- Baoding Zhang (ORCID: https://orcid.org/0000-0002-6011-9930)
- Yong Yu (ORCID: https://orcid.org/0000-0002-9821-9726)
- Jin-Wei Feng
- Chen‐Song Zhang (ORCID: https://orcid.org/0000-0001-5218-0101)
- Zheni Xu (ORCID: https://orcid.org/0000-0001-7926-0259)
- Cixiong Zhang
- Xiao Tian (ORCID: https://orcid.org/0000-0001-5300-3596)
- Weiche Wang
- Junjie Chen (ORCID: https://orcid.org/0000-0002-3046-4821)
- Yan Chen (ORCID: https://orcid.org/0000-0001-5325-1151)
- Liyun Lin
- Beibei Sun (ORCID: https://orcid.org/0000-0002-6007-8550)
- Zhenhua Wu (ORCID: https://orcid.org/0000-0003-4552-883X)
- Mengqi Li (ORCID: https://orcid.org/0000-0002-1171-5648)
- Huayu Tian (ORCID: https://orcid.org/0000-0002-2482-3744)
- Liu Yanhui (ORCID: https://orcid.org/0000-0001-9061-2788)
- Yu Wang (ORCID: https://orcid.org/0009-0009-2984-2344)
- Xiaoyan Wei (ORCID: https://orcid.org/0000-0001-9168-1048)
- Qi Qu (ORCID: https://orcid.org/0000-0002-4870-6606)
- Yaying Wu
- ZK Xie
- Shengrong Xu
- Yuanji Feng
- Heng-Ye Yang
Institutions
- Dalian Institute of Chemical Physics (CN)
- Xiamen University (CN)
- Chinese Academy of Sciences (CN)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s41586-024-08348-2
- Citations
- 67
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 23.06