Interaction between Hormone-Sensitive Lipase and ChREBP in Fat Cells Controls Insulin Sensitivity
Résumé
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
Domaines
Endocrinologie et métabolisme
Fichier principal
NatureMetabolismAcceptedVersion.pdf (2.08 Mo)
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SupplementaryInformation.pdf (13.34 Mo)
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