Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, United States.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, United States.
Am J Physiol Gastrointest Liver Physiol. 2023 Dec 1;325(6):G582-G592. doi: 10.1152/ajpgi.00235.2022. Epub 2023 Oct 17.
Zinc fingers and homeoboxes 2 () are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified targets become dysregulated in liver damage, we investigated the relationship between and in liver development, damage, and regeneration. Here, using mouse and cell models, we demonstrate that positively regulates expression in the liver and that male-biased hepatic expression is established between 4 and 8 wk of age in mice. is dramatically repressed in mouse models of liver regeneration, and the reduced levels in the regenerating liver are associated with changes in hepatic VLCFAs. Human hepatoma cell lines with forced expression have lower rates of cell growth; analysis of synchronized cells indicates that this reduced proliferation correlates with cells stalling in S-phase and lower mRNA levels of cell cyclins. Taken together, these data indicate that expression helps regulate cellular proliferation during liver development and regeneration, possibly through control of VLCFAs. Numerous targets of the transcription factor are dysregulated in liver disease. We show that the elongase is a novel target. and expression change during liver regeneration, which is associated with changes in very long chain fatty acids. Forced expression reduces cell growth and blocks cell cycle progression. This suggests that may account, at least in part, for the relationship between and proliferation during liver development and disease.
锌指和同源盒 2 () 是肝脏基因表达的转录调节因子，在胚胎发育以及组织再生中具有关键功能，这可能是通过对靶基因的控制来实现的。先前的微阵列数据表明，延伸超长链脂肪酸-3 ()，一种合成超长链脂肪酸 (VLCFAs) 的 ELOVL 酶家族的成员，是一个假定的靶基因。VLCFAs 是神经酰胺和其他生物活性神经鞘脂的核心成分，这些物质在疾病中经常失调，并调节包括增殖在内的关键细胞过程。由于先前鉴定的几个靶基因在肝损伤中失调，我们研究了 与肝脏发育、损伤和再生中的 之间的关系。在这里，我们使用小鼠和细胞模型，证明 正向调节肝脏中的 表达，并且雄性偏倚的肝 表达在小鼠 4 至 8 周龄之间建立。在肝脏再生的小鼠模型中， 显著受到抑制，再生肝脏中的 水平降低与肝 VLCFAs 的变化有关。具有强制 表达的人肝癌细胞系的细胞生长率较低；对同步化细胞的分析表明，这种增殖减少与 S 期停滞和细胞周期蛋白的 mRNA 水平降低相关。综上所述，这些数据表明， 在肝脏发育和再生过程中有助于调节细胞增殖，可能是通过控制 VLCFAs 来实现的。转录因子 的许多靶基因在肝脏疾病中失调。我们表明，延伸酶 是一个新的 靶基因。 和 表达在肝脏再生过程中发生变化，这与超长链脂肪酸的变化有关。强制 表达降低细胞生长并阻止细胞周期进程。这表明 至少部分解释了 在肝脏发育和疾病过程中与增殖之间的关系。
