Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.

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.

• Authors: Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Fadila Benhamed, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Sam Virtue, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Sandra Guilmeau, Valentin Barquissau, Diane Beuzelin, Sophie Bonnel, Marie Marques, Boris Monge-Roffarello, Corinne Lefort, Barbara Fielding, Thierry Sulpice, Arne Astrup, Bernard Payrastre, Justine Bertrand-Michel, Emmanuelle Meugnier, Laetitia Ligat, Frédéric Lopez, Hervé Guillou, Charlotte Ling, Cecilia Holm, Remi Rabasa-Lhoret, Wim H M Saris, Vladimir Stich, Peter Arner, Mikael Rydén, Cedric Moro, Nathalie Viguerie, Matthew Harms, Stefan Hallén, Antonio Vidal-Puig, Hubert Vidal, Catherine Postic, Dominique Langin
• Journal: Nature metabolism (Nat Metab) Vol. 1 Issue 1 Pg. 133-146 (01 2019) ISSN: 2522-5812 [Electronic] Germany
• PMID: 32694809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Biomarkers
• Elovl6 protein, mouse
• Insulin
• Mlxipl protein, mouse
• Fatty Acid Elongases
• Sterol Esterase
• Glucose

Topics

• Adipocytes (metabolism)
• Adipose Tissue (metabolism)
• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Biomarkers
• Fatty Acid Elongases (genetics, metabolism)
• Gene Expression
• Glucose (metabolism)
• Insulin (metabolism)
• Insulin Resistance (genetics)
• Membrane Fluidity (genetics)
• Mice
• Mice, Transgenic
• Protein Interaction Mapping
• Protein Interaction Maps
• Signal Transduction
• Sterol Esterase (metabolism)