Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France.
Nat Metab. 2019 Jan;1(1):133-146. doi: 10.1038/s42255-018-0007-6. Epub 2018 Dec 3.
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.
脂肪组织胰岛素信号转导受损是胰岛素抵抗的一个关键特征。在这里，我们确定了一条途径，通过葡萄糖反应性转录因子 ChREBP 及其靶标脂肪酸延长酶 ELOVL6，将脂肪分解酶激素敏感脂肪酶 (HSL) 与胰岛素作用联系起来。在人脂肪细胞和小鼠脂肪组织中遗传抑制 HSL 会导致胰岛素敏感性增强和 ELOVL6 的诱导。ELOVL6 促进磷脂油酸的增加，从而改变质膜流动性并增强胰岛素信号转导。HSL 缺乏介导的作用可通过 ChREBP 和 ELOVL6 的基因沉默来抑制。从机制上讲，HSL 与 ChREBPα 的物理相互作用，独立于脂肪酶活性，ChREBPα 是由葡萄糖代谢激活的同工型，会损害 ChREBPα 向核内的易位和 ChREBPβ 的诱导，ChREBPβ 是具有高转录活性的同工型，与全身胰岛素敏感性密切相关。靶向 HSL-ChREBP 相互作用可能为恢复胰岛素敏感性提供治疗策略。
