Conserved statin-mediated activation of the p38-MAPK pathway protects Caenorhabditis elegans from the cholesterol-independent effects of statins

Irina Langier Goncalves, Sharon Tal, Liza Barki-Harrington, Amir Sapir

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Statins are a group of medications that reduce cholesterol synthesis by inhibiting the activity of HMG-CoA reductase, a key enzyme in the mevalonate pathway. The clinical use of statins to lower excess cholesterol levels has revolutionized the cardiovascular field and increased the survival of millions, but some patients have adverse side effects. A growing body of data suggests that some of the beneficial and adverse effects of statins, including their anti-inflammatory, anti-tumorigenic, and myopathic activities, are cholesterol-independent. However, the underlying mechanisms for these effects of statins are not well defined. Methods: Because Caenorhabditis elegans (C. elegans) lacks the cholesterol synthesis branch of the mevalonate pathway, this organism is a powerful system to unveil the cholesterol-independent effects of statins. We used genetic and biochemical approaches in C. elegans and cultured macrophage-derived murine cells to study the cellular response to statins. Results: We found that statins activate a conserved p38-MAPK (p38) cascade and that the protein geranylgeranylation branch of the mevalonate pathway links the effect of statins to the activation of this p38 pathway. We propose that the blockade of geranylgeranylation impairs the function of specific small GTPases we identified as upstream regulators of the p38 pathway. Statin-mediated p38 activation in C. elegans results in the regulation of programs of innate immunity, stress, and metabolism. In agreement with this regulation, knockout of the p38 pathway results in the hypersensitivity of C. elegans to statins. Treating cultured mammalian cells with clinical doses of statins results in the activation of the same p38 pathway, which upregulates the COX-2 protein, a major regulator of innate immunity in mammals. Conclusions: Statins activate an evolutionarily conserved p38 pathway to regulate metabolism and innate immunity. Our results highlight the cytoprotective role of p38 activation under statin treatment in vivo and propose that this activation underlies many of the critical cholesterol-independent effects of statins.

Original languageEnglish
Article number101003
JournalMolecular Metabolism
Volume39
DOIs
StatePublished - Sep 2020

Bibliographical note

Funding Information:
Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs ( P40 OD010440 ). We are grateful to Drs. Cole Haynes (UMass, Amherst, MA, USA), Paul. W. Sternberg (Caltech, Pasadena, CA, USA), Shane L. Rea (UW, Seattle, WA, USA), and Sivan Henis-Korenblit (Bar-Ilan University, Ramat Gan, Israel) for C. elegans strains. We thank Drs. Yoram Gercheman, Elah Pick, Shamsuzzama, and Mr. Benjamin Trabelsi (all from the University of Haifa, Haifa, Israel) for reagents and assistance with the analysis of the RT-qPCR results. We thank Drs. Limor Broday (Tel Aviv University, Tel Aviv, Israel) and Benjamin Podbilewicz (Technion-Israel Institute of Technology, Haifa, Israel) for providing reagents. We are grateful to Drs. Ayelet Lamm, Roni Hass, and Guy Horev (Technion-Israel Institute of Technology, Haifa, Israel) and Dr. Maya Lalzar (University of Haifa, Haifa, Israel) for assistance with the analysis of RNA-seq data. This study was supported by the Israel Science Foundation (ISF) grants 1747/16 to AS and 2240/19 to LBH.

Funding Information:
Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). We are grateful to Drs. Cole Haynes (UMass, Amherst, MA, USA), Paul. W. Sternberg (Caltech, Pasadena, CA, USA), Shane L. Rea (UW, Seattle, WA, USA), and Sivan Henis-Korenblit (Bar-Ilan University, Ramat Gan, Israel) for C. elegans strains. We thank Drs. Yoram Gercheman, Elah Pick, Shamsuzzama, and Mr. Benjamin Trabelsi (all from the University of Haifa, Haifa, Israel) for reagents and assistance with the analysis of the RT-qPCR results. We thank Drs. Limor Broday (Tel Aviv University, Tel Aviv, Israel) and Benjamin Podbilewicz (Technion-Israel Institute of Technology, Haifa, Israel) for providing reagents. We are grateful to Drs. Ayelet Lamm, Roni Hass, and Guy Horev (Technion-Israel Institute of Technology, Haifa, Israel) and Dr. Maya Lalzar (University of Haifa, Haifa, Israel) for assistance with the analysis of RNA-seq data. This study was supported by the Israel Science Foundation (ISF) grants 1747/16 to AS and 2240/19 to LBH.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • C. elegans
  • COX-2
  • Cholesterol-independent effect
  • Geranylgeranylation
  • Innate immunity.
  • Mevalonate pathway
  • Small GTPases
  • Statins
  • p38 pathway

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Conserved statin-mediated activation of the p38-MAPK pathway protects Caenorhabditis elegans from the cholesterol-independent effects of statins'. Together they form a unique fingerprint.

Cite this