Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice
- University Medical Center Groningen, Netherlands
- Leibniz Institute on Ageing - Fritz Lipmann Institute, Germany
- University of Ulm, Germany
- Utrecht University, Netherlands
Abstract
Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPβ-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-mRNA. Here we describe that reduced C/EBPβ-LIP expression due to genetic ablation of the uORF delays the development of age-associated phenotypes in mice. Moreover, female C/EBPβΔuORF mice display an extended lifespan. Since LIP levels increase upon aging in wild type mice, our data reveal an important role for C/EBPβ in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPβ-LIP may offer new possibilities to treat age-related diseases and to prolong healthspan.
Data availability
For transcriptome dataset see: Müller, C., de Jong, T, Guryev, V, Calkhoven, CF. (2018). Transcriptome profiling of liver samples of C/EBPβΔuORF mice. Retrieved from: https://www.ebi.ac.uk/arrayexpress/
Article and author information
Author details
Cornelis F Calkhoven
Funding
Deutsche Forschungsgemeinschaft (CA 283/1-1)
- Laura M Zidek
- Cornelis F Calkhoven
Leibniz-Gemeinschaft (LGSA)
- Tobias Ackermann
- Cornelis F Calkhoven
Deutsche Forschungsgemeinschaft (MA 3975/2-1)
- Laura M Zidek
- Julia von Maltzahn
Deutsche Forschungsgemeinschaft (INST 40/492-1)
- Peng Liu
- Jan P Tuckermann
Deutsche Forschungsgemeinschaft (TU 220/6)
- Peng Liu
- Jan P Tuckermann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Thüringer Landesamt für Verbraucherschutz (#03-005/13) and University of Groningen (#6996A).
Copyright
© 2018, Müller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice
eLife 7:e34985.
https://doi.org/10.7554/eLife.34985
Further reading
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De novo lipogenesis is associated with the development of human diseases such as cancer, diabetes, and obesity. At the core of lipogenesis lies acetyl coenzyme A (CoA), a metabolite that plays a crucial role in fatty acid synthesis. One of the pathways contributing to the production of cytosolic acetyl-CoA is mediated by acetyl-CoA synthetase 2 (ACSS2). Here, we reveal that when cells encounter nutrient stress, particularly a deficiency in amino acids, Sirtuin 2 (SIRT2) catalyzes the deacetylation of ACSS2 at the lysine residue K271. This results in K271 ubiquitination and subsequently proteasomal degradation of ACSS2. Substitution of K271 leads to decreased ubiquitination of ACSS2, increased ACSS2 protein level, and thus increased lipogenesis. Our study uncovers a mechanism that cells employ to efficiently manage lipogenesis during periods of nutrient stress.
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