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Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder
Minsoo Kang , Sun Kyoung Han , Suhyun Kim , Sungyeon Park , Yerin Jo , Hyeryung Kang , Jesang Ko*
Division of Life Sciences, Korea University, Seoul 02841, South Korea
*Correspondence to:Jesang Ko , Email:jesangko@korea.ac.kr
J Mol Cell Biol, Volume 13, Issue 5, May 2021, Pages 361-373  https://doi.org/10.1093/jmcb/mjaa069
Keyword: gluconeogenic enzymes, hepatic gluconeogenesis, hyperglycemia, transcription factor

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.