Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Bialystok, Poland.
Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Bialystok, Poland.
PLoS One. 2024 Aug 23;19(8):e0307802. doi: 10.1371/journal.pone.0307802. eCollection 2024.
Prolonged consumption of diet rich in fats is regarded as the major factor leading to the insulin resistance (IR) and type 2 diabetes (T2D). Emerging evidence link excessive accumulation of bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer), with impairment of insulin signaling in skeletal muscle. Until recently, little has been known about the involvement of long-chain acyl-CoAs synthetases in the above mechanism. To examine possible role of long-chain acyl-coenzyme A synthetase 1 (Acsl1) (a major muscular ACSL isoform) in mediating HFD-induced IR we locally silenced Acsl1 in gastrocnemius of high-fat diet (HFD)-fed C57BL/6J mice through electroporation-delivered shRNA and compared it to non-silenced tissue within the same animal. Acsl1 down-regulation decreased the content of muscular long-chain acyl-CoA (LCACoA) and both the Cer (C18:1-Cer and C24:1-Cer) and DAG (C16:0/18:0-DAG, C16:0/18:2-DAG, C18:0/18:0-DAG) and simultaneously improved insulin sensitivity and glucose uptake as compared with non-silenced tissue. Acsl1 down-regulation decreased expression of mitochondrial β-oxidation enzymes, and the content of both the short-chain acylcarnitine (SCA-Car) and short-chain acyl-CoA (SCACoA) in muscle, pointing towards reduction of mitochondrial FA oxidation. The results indicate, that beneficial effects of Acsl1 partial ablation on muscular insulin sensitivity are connected with inhibition of Cer and DAG accumulation, and outweigh detrimental impact of decreased mitochondrial fatty acids metabolism in skeletal muscle of obese HFD-fed mice.
长期摄入高脂肪饮食被认为是导致胰岛素抵抗（IR）和 2 型糖尿病（T2D）的主要因素。新出现的证据表明，生物活性脂质如二酰基甘油（DAG）和神经酰胺（Cer）的过度积累与骨骼肌胰岛素信号转导受损有关。直到最近，人们对长链酰基辅酶 A 合成酶（LCACS）在上述机制中的参与知之甚少。为了研究长链酰基辅酶 A 合成酶 1（Acsl1）（主要的肌肉 ACSL 同工型）在介导高脂肪饮食（HFD）诱导的 IR 中的可能作用，我们通过电穿孔递送 shRNA 在 HFD 喂养的 C57BL/6J 小鼠的比目鱼肌中局部沉默 Acsl1，并将其与同一动物的未沉默组织进行比较。Acsl1 下调降低了肌肉长链酰基辅酶 A（LCACoA）的含量，以及神经酰胺（C18:1-Cer 和 C24:1-Cer）和 DAG（C16:0/18:0-DAG、C16:0/18:2-DAG、C18:0/18:0-DAG）的含量，同时与未沉默组织相比，胰岛素敏感性和葡萄糖摄取得到改善。Acsl1 下调降低了线粒体 β-氧化酶的表达，以及肌肉中短链酰基辅酶 A（SCA-Car）和短链酰基辅酶 A（SCACoA）的含量，表明线粒体 FA 氧化减少。结果表明，Acsl1 部分消融对肌肉胰岛素敏感性的有益影响与 Cer 和 DAG 积累的抑制有关，并且超过了肥胖 HFD 喂养小鼠骨骼肌中线粒体脂肪酸代谢减少的不利影响。
