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

Abstract

Impaired adipose tissue insulin signaling 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 (FA) 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 (PL) oleic acid which modifies plasma membrane fluidity and enhances insulin signaling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL and ChREBPα, independently of lipase catalytic activity, impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the transcriptionally highly active isoform strongly associated to whole body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity. Morigny, Houssier et al.

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

“…40,41 Palmitate is also a precursor of ceramides and other lipotoxic lipids. 42 Excess fructose is only in part used for DNL and can also be metabolised as uric acid through the purine cycle ( Fig. 2).…”

The Lipolysome—A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation

“…Thereby, HSL retains ChREBP in the cytoplasm, preventing its nuclear translocation and subsequent transcriptional induction of target genes such as the FA elongase ELOVL6, an enzyme catalyzing the elongation of palmitic acid to stearic acid, which can be further desaturated into oleic acid. By contrast, the partial inhibition of HSL, which was shown to improve insulin sensitivity in murine AT and human adipocytes [167,168], increases ELOVL6 expression. As a consequence, increased amounts of oleic acid are incorporated into phospholipids.…”

“…In humans, the expression of ChREBP and adipose DNL are positively associated with insulin sensitivity [165,166]. Recently, an exciting study demonstrated a direct interaction between HSL and ChREBP regulating insulin signaling in white adipocytes [167]. Thereby, HSL retains ChREBP in the cytoplasm, preventing its nuclear translocation and subsequent transcriptional induction of target genes such as the FA elongase ELOVL6, an enzyme catalyzing the elongation of palmitic acid to stearic acid, which can be further desaturated into oleic acid.…”

“…Morigny et al [167] further showed that an enzymatically inactive form of HSL represses ChREBP activity as well, indicating that the protein-protein interaction depends on the presence of HSL but not on its lipolytic activity. However, it is still elusive as to which part of HSL binds to ChREBP and whether the phosphorylation of the lipase modifies their interaction.…”

Un partenariat inattendu dans l’adipocyte

“…Néanmoins, les taux circulants d'acides gras étant inchangés chez ces animaux, les mécanismes impliqués dans ces effets bénéfiques restaient incompris. Dans une étude récemment publiée dans la revue Nature Metabolism, nous montrons qu'une invalidation partielle de la LHS dans des adipocytes humains en culture favorise l'entrée du glucose dans la cellule ainsi que son utilisation pour la synthèse d'acides gras (lipogenèse de novo), et améliore la transmission du signal insulinique [8]. En utilisant des inhibiteurs pharmacologiques des enzymes de la lipogenèse de novo, nous avons constaté que l'activation de cette voie est essentielle aux effets bénéfiques de l'invalidation de la LHS sur la sensibilité à l'insuline.…”