收稿日期: 2024-03-01
录用日期: 2024-06-10
网络出版日期: 2024-10-28
基金资助
上海市自然科学基金(20ZR1442500)
Advances of GADD45b in hepatic glucose and lipid metabolism
Received date: 2024-03-01
Accepted date: 2024-06-10
Online published: 2024-10-28
Supported by
Natural Science Foundation of Shanghai(20ZR1442500)
生长阻滞和DNA损伤诱导因子45b(growth arrest and DNA damage inducible 45b,GADD45b)最初被发现参与细胞周期阻滞、分化与凋亡等过程,是细胞中重要的信号调节分子,承担细胞在多种生理或环境刺激下的信号转导功能。GADD45b基因隶属于GADD45基因家族,该基因在人体与胎儿组织中普遍表达,但表达具有组织差异性,其中在肝脏与骨髓高表达。GADD45b蛋白是一类体积小、进化保守的酸性蛋白质,在细胞质/胞核中均有分布。研究表明,GADD45b与丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)、转化生长因子β(transforming growth factor β,TGFβ)等信号通路关系密切,并且具有改善组织纤维化与炎症进展、抑制细胞自噬、提高神经功能恢复等功能,在肿瘤、先天免疫、神经系统疾病、肝脏糖脂代谢紊乱等方面发挥重要作用。非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)发病率逐年升高,已成为我国严重的公共卫生问题。肝脏糖脂代谢障碍是导致NAFLD的重要原因。多个研究均表明肝脏糖脂代谢障碍与肝疾病中存在GADD45b基因与蛋白的异常表达。既往研究发现,GADD45b可以增加肝细胞叉头盒转录因子O1(forkhead box O1,FoxO1)稳定性、提高过氧化物酶体增殖物激活受体γ共激活剂1a(peroxisome proliferator-activated receptor-gamma coactivator1a,PGC1a)表达进而促进肝脏糖异生;并且GADD45b还可以通过结合脂肪酸结合蛋白1(fatty acid binding protein 1,FABP1)抑制肝细胞脂肪酸转运,与热休克蛋白72(heat shock protein72,HSP72)蛋白结合降低肝脏脂肪变性程度。因此,GADD45b促进肝脏糖异生、抑制脂肪酸转运以及降低脂肪变性的作用,可能是治疗肝脏糖脂代谢障碍及肝疾病的研究基础。该文综述GADD45b蛋白的特征、功能以及在肝脏糖脂代谢与肝疾病研究中的新进展,以期为进一步的GADD45b研究提供参考。
关键词: 生长阻滞和DNA损伤诱导因子45b(GADD45b); 糖脂代谢; 代谢障碍; 非酒精性脂肪性肝病
王仁杰 , 花慧 , 祝超瑜 , 魏丽 . GADD45b在肝脏糖脂代谢中作用的研究进展[J]. 上海交通大学学报(医学版), 2024 , 44(10) : 1316 -1322 . DOI: 10.3969/j.issn.1674-8115.2024.10.014
Growth arrest and DNA damage-inducible 45b (GADD45b) was initially discovered to be involved in processes such as cell cycle arrest, differentiation and apoptosis. It is an important signal regulatory molecule in cells, responsible for signal transduction under various physiological or environmental stimuli. The GADD45b gene belongs to the GADD45 gene family. This gene is commonly expressed in human and fetal tissues, but the expression is tissue-specific, with high expression in the liver and bone marrow. The GADD45b protein is a small, evolutionarily conserved acidic protein distributed in both the cytoplasm and nucleus. Research has shown that GADD45b is closely associated with signaling pathways such as p38/MAPK and TGFβ/Smad3, and it has functions including improving tissue fibrosis and inflammation progression, inhibiting cell autophagy, and enhancing neural function recovery. GADD45b plays a significant role in tumors, innate immunity, neurological diseases, and disorders of hepatic glucose and lipid metabolism. The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing year by year in China and has become a serious public health issue in the country. Disorders in hepatic glucose and lipid metabolism are major causes of NAFLD. Multiple studies have shown that GADD45b gene and protein exhibit abnormal expression in liver diseases with hepatic glucose and lipid metabolism disorders. Previous research has found that GADD45b can increase the stability of the FoxO1 protein in hepatocytes, and enhance the expression of PGC1a, thereby promoting hepatic gluconeogenesis. Additionally, GADD45b can inhibit fatty acid transport in hepatocytes by binding to FABP1 and reduce hepatic steatosis by interacting with HSP72 protein. Therefore, the roles of GADD45b in promoting hepatic gluconeogenesis, inhibiting fatty acid transport, and reducing steatosis may form the basis for research into treatments for hepatic glucose and lipid metabolism disorders and liver diseases. This paper reviews the characteristics and functions of the GADD45b protein, as well as recent advances in the study of hepatic glucose and lipid metabolism and liver diseases, aiming to provide reference for further GADD45b research.
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