<br>DGAT1 和 DGAT2 在人类肌管中的作用取决于供体病理生理背景,The FASEB Journal

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DGAT1 和 DGAT2 在人类肌管中的作用取决于供体病理生理背景
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-10-01 , DOI: 10.1096/fj.202300960rr
Zehra Irshad ₁ , Jenny Lund ₂ , Anne Sillars ₃ , Nils Gunnar Løvsletten ₂ , Seley Gharanei _{1,

4} , Ian P Salt ₅ , Dilys J Freeman ₃ , Jason M R Gill ₃ , G Hege Thoresen _{2,

6} , Arild C Rustan ₂ , Victor A Zammit ₁

Affiliation

使用冰冻切片和肌管，研究 DGAT1 和 DGAT2 在人类骨骼肌脂质代谢和胰岛素反应性中的作用，这些冰冻切片和肌管是从对照、运动员和血糖调节受损 (IGR) 男性群体的肌肉活检中制备的。先前观察到的运动员和 IGR 肌内三酰甘油 (IMTG) 的增加与运动员 I 型纤维中脂滴 (LD) 面积的增加有关，但相反，与 IGR 受试者中 II 型纤维中脂滴 (LD) 面积的增加有关。特异性抑制二酰基甘油酰基转移酶 (DGAT) 1 和 2 会减少肌管对脂肪酸 (FA) 的摄取，而仅抑制 DGAT2 也会减少脂肪酸氧化。肌管中的脂肪酸摄取与各个供体的乳酸阈值呈负相关。 DGAT2 抑制降低了所有组的肌管中乙酸盐的摄取和氧化，而 DGAT1 抑制则没有效果。观察到肌管中的乙酸盐氧化与体内脂肪酸氧化的静息代谢率（RMR）呈正相关。运动员和 IGR 的肌管具有较高的醋酸盐从头脂肪生成率，通过抑制 DGAT2 使其正常化。此外，肌管中的 DGAT2 抑制也会导致胰岛素诱导的 Akt 磷酸化增加。 DGAT1 和 DGAT2 抑制的不同作用表明，DGAT2 在酯化新生二酰基甘油和从头合成的 FA 中的特殊作用与三酰基甘油池的合成有关，三酰基甘油池在水解后会产生促进线粒体脂肪酸氧化但减少胰岛素信号传导的效应物在骨骼肌细胞中。

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The roles of DGAT1 and DGAT2 in human myotubes are dependent on donor patho-physiological background

The roles of DGAT1 and DGAT2 in lipid metabolism and insulin responsiveness of human skeletal muscle were studied using cryosections and myotubes prepared from muscle biopsies from control, athlete, and impaired glucose regulation (IGR) cohorts of men. The previously observed increases in intramuscular triacylglycerol (IMTG) in athletes and IGR were shown to be related to an increase in lipid droplet (LD) area in type I fibers in athletes but, conversely, in type II fibers in IGR subjects. Specific inhibition of both diacylglycerol acyltransferase (DGAT) 1 and 2 decreased fatty acid (FA) uptake by myotubes, whereas only DGAT2 inhibition also decreased fatty acid oxidation. Fatty acid uptake in myotubes was negatively correlated with the lactate thresholds of the respective donors. DGAT2 inhibition lowered acetate uptake and oxidation in myotubes from all cohorts whereas DGAT1 inhibition had no effect. A positive correlation between acetate oxidation in myotubes and resting metabolic rate (RMR) from fatty acid oxidation in vivo was observed. Myotubes from athletes and IGR had higher rates of de novo lipogenesis from acetate that were normalized by DGAT2 inhibition. Moreover, DGAT2 inhibition in myotubes also resulted in increased insulin-induced Akt phosphorylation. The differential effects of DGAT1 and DGAT2 inhibition suggest that the specialized role of DGAT2 in esterifying nascent diacylglycerols and de novo synthesized FA is associated with synthesis of a pool of triacylglycerol, which upon hydrolysis results in effectors that promote mitochondrial fatty acid oxidation but decrease insulin signaling in skeletal muscle cells.

更新日期：2023-10-02

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