Minemura Tomomi, Fukuhara Atsunori, Otsuki Michio, Shimomura Iichiro
Osaka University Graduate School of Frontier Biosciences, Japan.
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Biochem Biophys Res Commun. 2022 Jun 4;607:20-27. doi: 10.1016/j.bbrc.2022.03.113. Epub 2022 Mar 24.
Plasma glucose levels are homeostatically regulated within strict boundaries and are maintained through a balance between peripheral glucose uptake and hepatic glucose production. However, little is known about the regulatory mechanism of glucose uptake in adipocytes during fasting. Under fasting conditions, the expression levels of 8 glycolytic enzymes were significantly reduced in adipose tissue. Among them, we focused on lactate dehydrogenase A (LDHA), the last enzyme of the glycolytic pathway. Under fasting conditions, both LDHA and Glut1 protein levels tended to decrease in adipose tissue. To elucidate the significance of LDHA in adipocytes, we generated adipocyte-specific LDHA knockout mice (AdLDHAKO) for the first time. AdLDHAKO mice showed no apparent changes in body weight or tissue weight. Under fasting conditions, AdLDHAKO mice exhibited a significant reduction in Glut1 protein levels and glucose uptake in adipose tissues compared with control mice. Similarly, siRNA of LDHA in 3T3-L1 adipocytes reduced Glut1 protein levels and basal glucose uptake. Moreover, treatment with bafilomycin A1, an inhibitor of lysosomal protein degradation, restored Glut1 protein levels by siRNA of LDHA. These results indicate that LDHA regulates Glut1 expression and basal glucose uptake in adipocytes.
血浆葡萄糖水平在严格的范围内进行稳态调节，并通过外周葡萄糖摄取与肝脏葡萄糖生成之间的平衡得以维持。然而，关于禁食期间脂肪细胞中葡萄糖摄取的调节机制，人们知之甚少。在禁食条件下，脂肪组织中8种糖酵解酶的表达水平显著降低。其中，我们重点关注糖酵解途径的最后一种酶——乳酸脱氢酶A（LDHA）。在禁食条件下，脂肪组织中LDHA和Glut1蛋白水平均有下降趋势。为阐明LDHA在脂肪细胞中的意义，我们首次构建了脂肪细胞特异性LDHA基因敲除小鼠（AdLDHAKO）。AdLDHAKO小鼠的体重和组织重量无明显变化。在禁食条件下，与对照小鼠相比，AdLDHAKO小鼠脂肪组织中的Glut1蛋白水平和葡萄糖摄取显著降低。同样，3T3-L1脂肪细胞中LDHA的siRNA降低了Glut1蛋白水平和基础葡萄糖摄取。此外，用溶酶体蛋白降解抑制剂巴弗洛霉素A1处理可通过LDHA的siRNA恢复Glut1蛋白水平。这些结果表明，LDHA调节脂肪细胞中Glut1的表达和基础葡萄糖摄取。
