학술논문
Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity
Document Type
Original Paper
Author
Morigny, Pauline; Houssier, Marianne; Mairal, Aline; Ghilain, Claire; Mouisel, Etienne; Benhamed, Fadila; Masri, Bernard; Recazens, Emeline; Denechaud, Pierre-Damien; Tavernier, Geneviève; Caspar-Bauguil, Sylvie; Virtue, Sam; Sramkova, Veronika; Monbrun, Laurent; Mazars, Anne; Zanoun, Madjid; Guilmeau, Sandra; Barquissau, Valentin; Beuzelin, Diane; Bonnel, Sophie; Marques, Marie; Monge-Roffarello, Boris; Lefort, Corinne; Fielding, Barbara; Sulpice, Thierry; Astrup, Arne; Payrastre, Bernard; Bertrand-Michel, Justine; Meugnier, Emmanuelle; Ligat, Laetitia; Lopez, Frédéric; Guillou, Hervé; Ling, Charlotte; Holm, Cecilia; Rabasa-Lhoret, Remi; Saris, Wim H. M.; Stich, Vladimir; Arner, Peter; Rydén, Mikael; Moro, Cedric; Viguerie, Nathalie; Harms, Matthew; Hallén, Stefan; Vidal-Puig, Antonio; Vidal, Hubert; Postic, Catherine; Langin, Dominique
Source
Nature Metabolism. 1(1):133-146
Subject
Language
English
ISSN
2522-5812
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.
Impaired adipocyte insulin signalling characterizes insulin resistance. Here the authors show that the hormone-sensitive lipase can sequester the glucose-responsive transcription factor ChREBP in the cytoplasm, which prevents transcription of its target ELOVL6, resulting in reduced insulin signalling.
Impaired adipocyte insulin signalling characterizes insulin resistance. Here the authors show that the hormone-sensitive lipase can sequester the glucose-responsive transcription factor ChREBP in the cytoplasm, which prevents transcription of its target ELOVL6, resulting in reduced insulin signalling.