| Literature DB >> 32694809 |
Pauline Morigny1,2, Marianne Houssier1,2, Aline Mairal1,2, Claire Ghilain1,2, Etienne Mouisel1,2, Fadila Benhamed3,4,5, Bernard Masri1,2, Emeline Recazens1,2, Pierre-Damien Denechaud1,2, Geneviève Tavernier1,2, Sylvie Caspar-Bauguil1,2,6, Sam Virtue7, Veronika Sramkova1,2,8,9, Laurent Monbrun1,2, Anne Mazars1,2, Madjid Zanoun1,2, Sandra Guilmeau3,4,5, Valentin Barquissau1,2, Diane Beuzelin1,2, Sophie Bonnel1,2,9, Marie Marques1,2,9, Boris Monge-Roffarello1,2, Corinne Lefort1,2, Barbara Fielding10, Thierry Sulpice11, Arne Astrup12, Bernard Payrastre1,2, Justine Bertrand-Michel1,2, Emmanuelle Meugnier13, Laetitia Ligat14, Frédéric Lopez14, Hervé Guillou15,16, Charlotte Ling17, Cecilia Holm18, Remi Rabasa-Lhoret19,20,21, Wim H M Saris22, Vladimir Stich8,9, Peter Arner23, Mikael Rydén23, Cedric Moro1,2,9, Nathalie Viguerie1,2,9, Matthew Harms24, Stefan Hallén24, Antonio Vidal-Puig7,25, Hubert Vidal13, Catherine Postic3,4,5, Dominique Langin26,27,28,29.
Abstract
Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.Entities:
Keywords: ChREBP; ELOVL Fatty Acid Elongase 6; ELOVL6 Expression; Hormone-sensitive Lipase; Insulin Signaling
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Year: 2018 PMID： 32694809 DOI： 10.1038/s42255-018-0007-6
Source DB: PubMed Journal: Nat Metab ISSN： 2522-5812