GADD45b在肝脏糖脂代谢中作用的研究进展

doi:10.3969/j.issn.1674-8115.2024.10.014

摘要/Abstract

摘要：

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

Abstract:

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.

Key words: growth arrest and DNA damage inducible 45b (GADD45b), glycolipid metabolism, metabolic disorder, non-alcoholic fatty liver disease

中图分类号:

R575.5

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.

WANG Renjie, HUA Hui, ZHU ChaoYu, WEI Li. Advances of GADD45b in hepatic glucose and lipid metabolism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1316-1322.

图/表 4

图1 禁食状态下小鼠肝脏GADD45b通过FoxO1对糖异生的影响

Fig 1 Effect of GADD45b on gluconeogenesis via FoxO1 in mouse liver during fasting

图2 GADD45b通过PGC1a调节肝脏糖异生

Fig 2 GADD45b regulates hepatic gluconeogenesis by PGC1a

图3 GADD45b通过FABP1对脂肪酸转运的影响

Fig 3 Effect of GADD45b on fatty acid transport through FABP1

图4 GADD45b通过SCD1对脂肪酸沉积的影响

Fig 4 Effect of GADD45b on steatosis via SCD1

参考文献 48

1	BEADLING C, JOHNSON K W, SMITH K A. Isolation of interleukin 2-induced immediate-early genes[J]. Proc Natl Acad Sci USA, 1993, 90(7): 2719-2723.
2	ABDOLLAHI A, LORD K A, HOFFMAN-LIEBERMANN B, et al. Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines[J]. Oncogene, 1991, 6(1): 165-167.
3	LIEBERMANN D A, HOFFMAN B. Gadd45 in stress signaling[J]. J Mol Signal, 2008, 3: 15.
4	KEARSEY J M, COATES P J, PRESCOTT A R, et al. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1[J]. Oncogene, 1995, 11(9): 1675-1683.
5	HILDESHEIM J, BULAVIN D V, ANVER M R, et al. Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53[J]. Cancer Res, 2002, 62(24): 7305-7315.
6	SULTAN F A, SAWAYA B E. Gadd45 in neuronal development, function, and injury[J]. Adv Exp Med Biol, 2022, 1360: 117-148.
7	TAMURA R E, DE VASCONCELLOS J F, SARKAR D, et al. GADD45 proteins: central players in tumorigenesis[J]. Curr Mol Med, 2012, 12(5): 634-651.
8	ZAIDI M R, LIEBERMANN D A. Gadd45 in senescence[J]. Adv Exp Med Biol, 2022, 1360: 109-116.
9	ZHAN Q, LORD K A, ALAMO I Jr, et al. The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth[J]. Mol Cell Biol, 1994, 14(4): 2361-2371.
10	HOFFMAN B, LIEBERMANN D A. Role of gadd45 in myeloid cells in response to hematopoietic stress[J]. Blood Cells Mol Dis, 2007, 39(3): 344-347.
11	ZHANG W, BAE I, KRISHNARAJU K, et al. CR6: a third member in the MyD118 and Gadd45 gene family which functions in negative growth control[J]. Oncogene, 1999, 18(35): 4899-4907.
12	FAGERBERG L, HALLSTRÖM B M, OKSVOLD P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics[J]. Mol Cell Proteomics, 2014, 13(2): 397-406.
13	BALLIET A G, HATTON K S, HOFFMAN B, et al. Comparative analysis of the genetic structure and chromosomal location of the murine MyD118 (Gadd45β) gene[J]. DNA Cell Biol, 2001, 20(4): 239-247.
14	VAIRAPANDI M, BALLIET A G, HOFFMAN B, et al. GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress[J]. J Cell Physiol, 2002, 192(3): 327-338.
15	SMITH M L, CHEN I T, ZHAN Q, et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen[J]. Science, 1994, 266(5189): 1376-1380.
16	SHI Y L, WANG J Y, HUANG G, et al. A novel epithelial-mesenchymal transition gene signature for the immune status and prognosis of hepatocellular carcinoma[J]. Hepatol Int, 2022, 16(4): 906-917.
17	KEIL E, HÖCKER R, SCHUSTER M, et al. Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy[J]. Cell Death Differ, 2013, 20(2): 321-332.
18	XUE M, SUN H X, XU R, et al. GADD45B promotes glucose-induced renal tubular epithelial-mesenchymal transition and apoptosis via the p38 MAPK and JNK signaling pathways[J]. Front Physiol, 2020, 11: 1074.
19	SHEN X Y, SHI S H, LI H, et al. The role of Gadd45b in neurologic and neuropsychiatric disorders: an overview[J]. Front Mol Neurosci, 2022, 15: 1021207.
20	DENG K P, FAN Y X, LIANG Y X, et al. FTO-mediated demethylation of GADD45B promotes myogenesis through the activation of p38 MAPK pathway[J]. Mol Ther Nucleic Acids, 2021, 26: 34-48.
21	MOON S J, KIM J H, CHOI Y K, et al. Ablation of Gadd45β ameliorates the inflammation and renal fibrosis caused by unilateral ureteral obstruction[J]. J Cell Mol Med, 2020, 24(15): 8814-8825.
22	ZHANG K M, ZHANG Q B, DENG J, et al. ALK5 signaling pathway mediates neurogenesis and functional recovery after cerebral ischemia/reperfusion in rats via Gadd45b[J]. Cell Death Dis, 2019, 10(5): 360.
23	SHAH A, WONDISFORD F E. Gluconeogenesis flux in metabolic disease[J]. Annu Rev Nutr, 2023, 43: 153-177.
24	MOUCHIROUD L, EICHNER L J, SHAW R J, et al. Transcriptional coregulators: fine-tuning metabolism[J]. Cell Metab, 2014, 20(1): 26-40.
25	FUHRMEISTER J, ZOTA A, SIJMONSMA T P, et al. Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health[J]. EMBO Mol Med, 2016, 8(6): 654-669.
26	KIM H, LEE D S, AN T H, et al. GADD45β regulates hepatic gluconeogenesis via modulating the protein stability of FoxO1[J]. Biomedicines, 2021, 9(1): 50.
27	WU L, JIAO Y, LI Y, et al. Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α[J]. J Exp Med, 2021, 218(5): e20201475.
28	LING C, RÖNN T. Epigenetics in human obesity and type 2 diabetes[J]. Cell Metab, 2019, 29(5): 1028-1044.
29	DONG Y X, MA N N, FAN L, et al. GADD45β stabilized by direct interaction with HSP72 ameliorates insulin resistance and lipid accumulation[J]. Pharmacol Res, 2021, 173: 105879.
30	LOOMBA R, FRIEDMAN S L, SHULMAN G I. Mechanisms and disease consequences of nonalcoholic fatty liver disease[J]. Cell, 2021, 184(10): 2537-2564.
31	ZHANG L T, LIU T J, HU C Z, et al. Proteome analysis identified proteins associated with mitochondrial function and inflammation activation crucially regulating the pathogenesis of fatty liver disease[J]. BMC Genomics, 2021, 22(1): 640.
32	WU J K, SHAO X H, SHEN J X, et al. Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells[J]. Int J Biol Sci, 2022, 18(14): 5438-5458.
33	MAN S, DENG Y H, MA Y, et al. Prevalence of liver steatosis and fibrosis in the general population and various high-risk populations: a nationwide study with 5.7 million adults in China[J]. Gastroenterology, 2023, 165(4): 1025-1040.
34	LIN H P, YIP T C, ZHANG X R, et al. Age and the relative importance of liver-related deaths in nonalcoholic fatty liver disease[J]. Hepatology, 2023, 77(2): 573-584.
35	YOUNOSSI Z M, HARRING M, YOUNOSSI Y, et al. The impact of NASH to liver transplantations with hepatocellular carcinoma in the United States[J]. Clin Gastroenterol Hepatol, 2022, 20(12): 2915-2917.e1.
36	ZHANG Z H, WANG S H, ZHU Z W, et al. Identification of potential feature genes in non-alcoholic fatty liver disease using bioinformatics analysis and machine learning strategies[J]. Comput Biol Med, 2023, 157: 106724.
37	YIP T C, FAN J G, WONG V W. China's fatty liver crisis: a looming public health emergency[J]. Gastroenterology, 2023, 165(4): 825-827.
38	JIANG Y, XIANG C, ZHONG F, et al. Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis[J]. Theranostics, 2021, 11(1): 361-378.
39	TZENG H T, CHYUAN I T, CHEN W Y. Shaping of innate immune response by fatty acid metabolite palmitate[J]. Cells, 2019, 8(12): 1633.
40	QIU W H, DAVID D, ZHOU B S, et al. Down-regulation of growth arrest DNA damage-inducible gene 45β expression is associated with human hepatocellular carcinoma[J]. Am J Pathol, 2003, 162(6): 1961-1974.
41	XIA H P, LEE K W, CHEN J X, et al. Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib[J]. Cell Death Discov, 2017, 3: 17058.
42	OU D L, SHEN Y C, YU S L, et al. Induction of DNA damage-inducible gene GADD45β contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells[J]. Cancer Res, 2010, 70(22): 9309-9318.
43	HOU X J, ZHAO Q D, JING Y Y, et al. Methylation mediated Gadd45β enhanced the chemosensitivity of hepatocellular carcinoma by inhibiting the stemness of liver cancer cells[J]. Cell Biosci, 2017, 7: 63.
44	GONG L Q, CAI L Q, LI G D, et al. GADD45B facilitates metastasis of ovarian cancer through epithelial-mesenchymal transition[J]. Onco Targets Ther, 2021, 14: 255-269.
45	CHEN L, KARISMA V W, LIU H W, et al. MicroRNA-300: a transcellular mediator in exosome regulates melanoma progression[J]. Front Oncol, 2019, 9: 1005.
46	NAPOLIONI V, BIANCONI F, POTENZA R, et al. Genome-wide expression of the residual lung reacting to experimental Pneumonectomy[J]. BMC Genomics, 2021, 22(1): 881.
47	WANG Q, WU W H, GAO Z, et al. GADD45B is a potential diagnostic and therapeutic target gene in chemotherapy-resistant prostate cancer[J]. Front Cell Dev Biol, 2021, 9: 716501.
48	YAO Z Y, CHEN Y, CAO W H, et al. Chromatin-modifying drugs and metabolites in cell fate control[J]. Cell Prolif, 2020, 53(11): e12898.

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