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Calorie mimetic activities of amino acids through regulation of C/EBPβ-LIP translation.
Keywords: cancer metabolism Calorie restriction
Researchers: Prof. dr. C.F. Calkhoven M.A. Zaini
Nature of the research: Molecular cell biology research to understand the role of specific mRNA translation in cell metabolism.
Fields of study: cell biology molecular biology

Background / introduction

Calorie restriction (CR) without malnutrition increases health and lifespan in virtually all species studied and it is thought that the beneficial effects of CR are mediated by mTORC1 signaling. However, recent research showed that it is not the calorie intake per se that is important but the ration of the macronutrients proteins vs. carbohydrates. The study shows that ratio of macronutrients dictates the cardio metabolic health, aging and longevity involving alters mTORC1 signaling. Branched chain amino acids and glucose are believed to be the main effector molecules in nutrient signaling (1-3). In our lab, we showed that specific translation into the C/EBPβ protein isoform LIP (Liver-specific Inhibitory Protein) is under control of mTORC1. C/EBPβ-LIP deficient mice display a CR-type improved metabolic profile, including reduced fat accumulation and increased fatty acid β-oxidation, improved insulin sensitivity and glucose tolerance, reduced cancer incidence and improved motor-coordination (4). Based on this mouse model we developed a reporter system to screen for and identify drugs that reduce the translation of C/EBPβ-LIP with potential calorie restriction mimetic activities (5). In this project we use the same reporter system, molecular biology techniques and metabolic assays to study the role of different amino acids in improving metabolic health by modulating mTORC1-C/EBPβ-LIP pathway.

Research question / problem definition
By using our C/EBPβ translation control reporter system we aim to identify the amino acids or other dietary conditions that may reduce the translation of C/EBPβ-LIP recapitulating the benefits of CR diet but without reducing the calorie intake.

Workplan

The project will be planned to be accomplished in the anticipated timeframe of the student’s stay in the lab and also to contribute to top-level publications. The technical expertise of our lab is extensive and thus students can learn a wide array of techniques across the disciplines of biochemistry, molecular biology and cellular metabolism. These include cell culturing, DNA transfection, protein purification, western blotting, luciferase assays, metabolic assays (using the Seahorse extracellular flux analyzer, microscopy, etc.
The student will be part of a highly motivated research team that provides excellent supervision and mentoring. In exchange we expect the student to be highly motivated and ambitious.

References

1- Solon-Biet, S.M. et al. (2014).The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418–430.
2- Solon-Biet, S.M. et al. (2015). Dietary protein to carbohydrate ratio and caloric restriction: comparing metabolic outcomes in mice. Cell Rep. 11, 1529–1534.
3- Fontana, L. et al. (2016). Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Reports 16, 520–530.
4- Zidek, L. M. et al. (2015) Deficiency in mTORC1-controlled C/EBPbeta-mRNA translation improves metabolic health in mice. EMBO Rep 16, 1022-1036, doi:10.15252/embr.201439837
5- Zaini, M.A. et al A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties. Scientific reports (under revision).

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