Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.
Pauline MorignyMarianne HoussierAline MairalClaire GhilainEtienne MouiselFadila BenhamedBernard MasriEmeline RecazensPierre-Damien DenechaudGeneviève TavernierSylvie Caspar-BauguilSam VirtueVeronika SramkovaLaurent MonbrunAnne MazarsMadjid ZanounSandra GuilmeauValentin BarquissauDiane BeuzelinSophie BonnelMarie MarquesBoris Monge-RoffarelloCorinne LefortBarbara FieldingThierry SulpiceArne AstrupBernard PayrastreJustine Bertrand-MichelEmmanuelle MeugnierLaetitia LigatFrédéric LopezHervé GuillouCharlotte LingCecilia HolmRemi Rabasa-LhoretWim H M SarisVladimir StichPeter ArnerMikael RydénCedric MoroNathalie ViguerieMatthew HarmsStefan HallénAntonio Vidal-PuigHubert VidalCatherine PosticDominique LanginPublished in: Nature metabolism (2018)
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.
Keyphrases
- adipose tissue
- insulin resistance
- type diabetes
- fatty acid
- transcription factor
- high fat diet
- glycemic control
- induced apoptosis
- cancer therapy
- endothelial cells
- physical activity
- mental health
- machine learning
- deep learning
- dna methylation
- dna binding
- copy number
- replacement therapy
- induced pluripotent stem cells
- endoplasmic reticulum stress