全反式维甲酸与肝脏疾病的关系及其分子机制研究进展  

Research progress in the relationship between all-trans retinoic acid and liver diseases and the associated molecular mechanisms

作　　者：许召君 陈小彬 才保加[2] 王成[2] 乔文杰 刘光照 王鑫乐 刘韬 马晓明[2] XU Zhaojun;CHEN Xiaobin;CAI Baojia;WANG Cheng;QIAO Wenjie;LIU Guangzhao;WANG Xinle;LIU Tao;MA Xiaoming(Graduate School of Qinghai University,Xining 810001,China;Department of Gastrointestinal Surgery,Affiliated Hospital of Qinghai University,Xining 810001,China)

机构地区：[1]青海大学研究生院,青海西宁810001 [2]青海大学附属医院胃肠外科,青海西宁810001

出　　处：《中国普通外科杂志》2021年第7期858-865,共8页China Journal of General Surgery

基　　金：国家重点研发计划基金资助项目(2017YFC0909900)。

摘　　要：全反式维甲酸(ATRA)也叫做视黄酸、维生素甲酸,是维生素A主要的生物活性形式,迄今为止ATRA在急性早幼粒细胞白血病(APL)中的应用已超过20年,并仍为APL治疗的标准方案。随着研究的不断深入,ATRA被广泛应用于甲状腺癌、肺癌、胃癌、卡波西氏肉瘤、卵巢癌、膀胱癌、神经母细胞瘤,等肿瘤的治疗中,且正逐步延伸至更多肿瘤的分化治疗。ATRA通过与核维甲酸受体(RAR)或维甲类X受体(RXR)结合并作用于维甲酸反应原件(RARE)从而调节基因的表达,在维持细胞稳态、调节细胞周期、信号转导、转录和翻译、调控肿瘤细胞的生长并促使其凋亡等发面发挥着重要的作用。肝脏是维生素A代谢的主要场所,相关研究显示,ATRA可通过调控相关蛋白(包括chemerin、信号蛋白Smad2/3、IGFBP-3等)以及遗传物质的表达,广泛参与肝炎、肝纤维化以及肝细胞癌的增殖、侵袭、凋亡等生物学过程。此外,ATRA可通过上调chemerin的表达来促进非酒精性脂肪性肝病的进展。肝星状细胞(HSC)也称为窦周细胞,是参与肝纤维化的主要细胞类型,当肝脏受损时,HSC可以转变为激活状态,活化的HSC通过分泌I型胶原蛋白(COL1α1)和α-平滑肌肌动蛋白(α-SMA),导致肝纤维化,而ATRA的活性形式维生素A可逆转HSC的激活和肝纤维化。一方面,Wnt信号通路通过激活HSC参与肝纤维化的形成,而ATRA可通过诱导RORα磷酸化,抑制Wnt/β-catenin的信号传递从而抑制肝纤维化的发生;另一方面,ATRA通过抑制TGF-β1/Smad信号通路的表达,从而发挥其抗肝纤维化作用。本文从多个途径阐述了ATRA抑制肝癌细胞的增殖并诱导其发生凋亡的机理,其中包括ATRA抑制Bcl-2和Bcl-x蛋白的表达从而诱导细胞发生凋亡的一系列过程,或直接充当诱导分化剂,诱导肝癌细胞发生凋亡的过程。此外,ATRA可通过调控相关遗传物质的表达来调节肝癌细胞的增值,其中包括通过�All-trans retinoic acid(ATRA), also called retinoic acid and vitamin formic acid, is the main biologically active form of vitamin A. So far, the application of ATRA in the treatment of acute promyelocytic leukemia(APL) has exceeded 20 years, which is still the standard treatment for APL. With the continuous deepening of research, ATRA has been widely used in the treatment of thyroid cancer, lung cancer, gastric cancer, Kaposi’s sarcoma, ovarian cancer, bladder cancer, neuroblastoma, and other tumors, and is gradually extending to the differentiation therapy for more tumors. ATRA regulates gene expression by binding to nuclear retinoic acid receptor(RAR) or retinoid X receptor(RXR) and acting on the retinoic acid response element(RARE). It plays an important role in maintaining cell homeostasis,regulating cell cycle, signal transduction, transcription and translation, regulating the growth of tumor cells and promoting their apoptosis. The liver is the main place for vitamin A metabolism. Related studies have shown that ATRA is widely involved in the biological processes such as hepatitis, liver fibrosis and liver cancer cell proliferation, invasion and apoptosis by regulating the expressions of related proteins(including chemerin, signal protein Smad2/3, IGFBP-3, etc.). In addition, ATRA can promote the progression of non-alcoholic fatty liver disease by up-regulating the expression of chemerin. Hepatic stellate cells(HSC), also known as pericytes, are the main cell type involved in liver fibrosis. When the liver is damaged, HSC can be transformed into an activated state. The activated HSC secretes type I collagen(COL1α1) and α-smooth muscle actin(α-SMA) and thereby causes liver fibrosis, and vitamin A, the active form of ATRA, can reverse HSC activation and liver fibrosis. On the one hand, the Wnt signaling pathway participates in the formation of liver fibrosis by activating HSC, while ATRA can inhibit the occurrence of liver fibrosis by inducing RORα phosphorylation and inhibiting the signal transmission

关 键 词：肝疾病 维甲酸 癌 肝细胞 非酒精性脂肪性肝病 肝硬化 

分 类 号：R657.3[医药卫生—外科学]