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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (1): 23-31    DOI: 10.3724/zdxbyxb-2021-0033
    
Cholesterol metabolism and tumor
MENG Ying1,2(),WANG Qifei1,2,LYU Zhimin1,2,*()
1. Zhejiang Provincial Key Laboratory of Pancreatic Disease,Department of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China;
2. Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China
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Abstract  

Cholesterol is an important lipid in the body of mammals and an essential component of membrane structures. Cholesterol homeostasis is critical for the maintenance of cellular and body activities, and is mainly regulated by the balance of de novo cholesterol biosynthesis and the exogenous cholesterol uptake. Aberrantly regulated cholesterol metabolism promotes tumor cell proliferation,survival,invasion and metastasis,and their adaptability into the tumor microenvironment. Therefore,targeting cholesterol biosynthesis and reduction of plasma cholesterol levels and cholesterol esterification will provide new strategies for cancer treatment. This review summarizes the current understanding in cholesterol homeostasis regulation and its function in the occurence and development of cancer,as well as current metabolism-targeted cancer treatments.



Key wordsCholesterol      Metabolism      Tumor      Therapy      Review     
Received: 25 November 2020      Published: 16 May 2021
CLC:  R73  
  R73  
  A  
Corresponding Authors: LYU Zhimin     E-mail: ymeng@zju.edu.cn;zhiminlu@zju.edu.cn
Cite this article:

MENG Ying,WANG Qifei,LYU Zhimin. Cholesterol metabolism and tumor. J Zhejiang Univ (Med Sci), 2021, 50(1): 23-31.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0033     OR     http://www.zjujournals.com/med/Y2021/V50/I1/23


胆固醇代谢与肿瘤

胆固醇是哺乳动物体内重要的脂质,是必不可少的膜结构成分。胆固醇稳态平衡对维持细胞和机体的生命活动至关重要,机体主要通过内源胆固醇的生物合成和外源胆固醇的摄取来获得胆固醇以维持自身稳态平衡。肿瘤细胞中胆固醇代谢异常活跃,导致其增殖、存活、侵袭、转移以及对肿瘤微环境的适应能力增强。靶向胆固醇合成、降低血浆胆固醇水平和胆固醇酯化的治疗策略将为肿瘤患者的治疗带来新的希望。本文总结了胆固醇代谢调节及其在肿瘤发生发展中的研究进展,并讨论了目前干扰胆固醇代谢的肿瘤治疗新方法。


关键词: 胆固醇,  代谢,  肿瘤,  治疗,  综述 
Figure 1 Cholesterol biosynthesis胆固醇的生物合成始于两分子的乙酰辅酶A,后者在硫解酶的作用下形成乙酰乙酰辅酶A,再通过β-羟基-β-甲戊二酸单酰辅酶A合酶(HMGCS)与第三分子的乙酰辅酶A缩合形成β-羟基-β-甲戊二酸单酰辅酶A(HMG-CoA);3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMGCR)将HMG-CoA还原成甲羟戊酸,甲羟戊酸进一步转化为法尼焦磷酸,法尼焦磷酸转化成角鲨烯并被角鲨烯单加氧酶氧化生成2,3-氧化角鲨烯,进而合成胆固醇.
Figure 2 Receptor-mediated cholesterol uptake 低密度脂蛋白(LDL)颗粒与LDL受体(LDLR)在细胞膜结合后,LDL-LDLR复合物首先通过内吞作用到达早期内体(EE);在酸性的EE中,LDLR与LDL颗粒分离返回至细胞膜循环利用,而LDL颗粒则进一步被转运至晚期内体(LE)并最终到达溶酶体;在溶酶体中,LDL来源的胆固醇酯被酸性脂肪酶水解,释放游离胆固醇,随后游离胆固醇被转运至溶酶体膜,并最终到达内质网进行传感、转运或酯化后储存于脂滴,同时也会被转运到线粒体、过氧化物酶体以及细胞膜等其他细胞器.高密度脂蛋白(HDL)颗粒与细胞膜上的B类Ⅰ型清道夫受体(SR-B1)结合后,SR-B1通过自身的疏水通道将HDL来源的胆固醇和胆固醇酯摄取到细胞质膜,并进一步转运到内质网等细胞器.酰基辅酶A:胆固醇酰基转移酶1.
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