Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China.
J Biol Chem. 2023 Jun;299(6):104795. doi: 10.1016/j.jbc.2023.104795. Epub 2023 May 5.
In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.
近年来，乳酸已被认为是一种重要的循环能量底物，而不仅仅是在低氧水平下葡萄糖氧化产生的死胡同代谢废物。“有氧糖酵解”一词被用来表示尽管氧气水平正常且功能线粒体正常，但葡萄糖摄取和乳酸生成增加。因此，在“有氧糖酵解”中，乳酸的产生是一种代谢选择，而在“无氧糖酵解”中，它是基于氧气水平不足的代谢必要性。有趣的是，乳酸可以被细胞摄取并氧化为丙酮酸，从而构成独立于胰岛素的丙酮酸来源。在这里，我们表明转录因子 Foxp1 调节脂肪细胞和肌细胞中的葡萄糖摄取和乳酸生成。Foxp1 的过表达导致葡萄糖摄取和乳酸生成增加。此外，糖酵解途径中的几种酶的蛋白水平上调，如己糖激酶 2、磷酸果糖激酶、醛缩酶和乳酸脱氢酶。通过染色质免疫沉淀和实时定量 PCR 分析，我们证明 Foxp1 直接与调节这些靶基因表达的启动子共识顺式元件相互作用。相反，Foxp1 的敲低抑制了这些酶的水平，降低了葡萄糖摄取和乳酸生成。此外，肌肉中 Foxp1 靶向缺失的小鼠表现出全身葡萄糖不耐受，肌肉葡萄糖摄取减少。在诱导表达 Foxp1 的原代人脂肪细胞中，我们发现糖酵解和糖酵解能力增加。我们的结果表明，Foxp1 可能作为脂肪组织和肌肉中有氧糖酵解的重要调节剂发挥作用。
