Division of Life Sciences, Korea University, Seoul 02841, South Korea.
J Mol Cell Biol. 2021 Aug 18;13(5):361-373. doi: 10.1093/jmcb/mjaa069.
Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.
肝糖异生是体内葡萄糖生成的核心途径。葡萄糖合成和摄取之间的失衡会导致代谢疾病，如肥胖、糖尿病和心血管疾病。小亮氨酸拉链蛋白（sLZIP）是 LZIP 的一种同工型，主要作为转录因子发挥作用。尽管 sLZIP 已知可以调节参与各种细胞过程的基因的转录，但它在肝葡萄糖代谢中的作用尚不清楚。在这项研究中，我们研究了 sLZIP 在肝糖异生中的调节作用及其在代谢紊乱中的参与。我们发现，sLZIP 在葡萄糖饥饿时表达增加，导致肝细胞中磷酸烯醇丙酮酸羧激酶和葡萄糖-6-磷酸酶的表达增加。然而，sLZIP 敲低抑制了低葡萄糖条件下糖异生酶的表达。sLZIP 还增强了人肝细胞和小鼠原代肝细胞中的葡萄糖生成。禁食诱导的环腺苷单磷酸阻止了 sLZIP 的降解。葡萄糖和丙酮酸耐量试验的结果表明，sLZIP 转基因小鼠表现出异常的血糖代谢。这些发现表明 sLZIP 是糖异生酶表达的新型调节因子，在饥饿期间参与血糖稳态的维持。
