Qu Q, Chen Y, Wang Y, Wang W, Long S, Yang HY, Wu J, Li M, Tian X, Wei X, Liu YH, Xu S, Xiong J, Yang C, Wu Z, Huang X, Xie C, Wu Y, Xu Z, Zhang C, Zhang B, Feng JW, Chen J, Feng Y, Fang H, Lin L, Xie ZK, Sun B, Tian H, Yu Y, Piao HL, Xie XS, Deng X, Zhang CS, Lin SC. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature. 2024 Dec 18; Epub 2024 Dec 18 PubMed.
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University of California, San Diego
These two studies by Qi et al. from Dr. Sheng-Cai Lin's group revealed a fundamental mechanism by which lithocholic acid mediates the pro-longevity effects of caloric restriction through the activation of AMPK, a key metabolic regulator. The discovery of LCA as a metabolic mediator of CR, and its effects across biochemical, cellular, and organismal levels, is truly striking. Moreover, the mechanistic study elegantly uncovered the molecular pathway underlying LCA-mediated AMPK activation: LCA binds to its receptor, TULP3, which activates sirtuins. These, in turn, inhibit vacuolar H⁺-ATPase on lysosomes, leading to AMPK activation. This novel signaling axis highlights the complex interplay between the deacetylation and phosphorylation of AMPK in response to glucose and nutrient-sensing signals.
Given AMPK’s well-established role in regulating glucose and lipid metabolism in the brain, these findings offer exciting new insights into neural health and disease. Alzheimer's disease in particular is associated with impaired glucose utilization and disrupted lipid metabolism, contributing to neuronal metabolic dysfunction and neuroinflammation. Both AMPK and sirtuins have been reported to directly and indirectly impact neuronal health, with both pathways linked to lysosomal function. Future investigations into the LCA-TULP3–sirtuin–v-ATPase–AMPK signaling pathway in neurons and glial cells during aging and neurological disorders could uncover new mechanistic insights into health and disease, while also informing potential translational strategies.
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