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A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties

//A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties

A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties

Nature | 15 February 2017 |

Summary

An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to  pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferasebased cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties.

Auteurs

Mohamad A. Zaini1, Christine Müller1, Tobias Ackermann1, Jeanette Reinshagen2, Gertrud Kortman1, Ole Pless2 & Cornelis F. Calkhoven1

Affiliaties

1European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD Groningen, The Netherlands. 2Fraunhofer IME ScreeningPort, D-22525 Hamburg, Germany.

Correspondence and requests for materials should be addressed to c.f.calkhoven@umcg.nl

2018-01-22T11:00:23+00:00