Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma
Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma
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异柠檬酸脱氢酶 1 突变增强神经胶质瘤中 24(S)-羟基胆固醇的产生并改变胆固醇稳态
DOI：
10.1038/s41388-020-01439-0
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发表时间：
2020-08
期刊：
影响因子：
8
通讯作者：
Ye Jing
中科院分区：
文献类型：
--
作者：
Yang Risheng;Zhao Yuanlin;Gu Yu;Yang Ying;Gao Xing;Yuan Yuan;Xiao Liming;Zhang Jin;Sun Chao;Yang Han;Qin Junhui;Li Jing;Zhang Feng;Zhang Lijun;Ye Jing
异柠檬酸脱氢酶(IDH)突变是胶质瘤发生中最重要的启动事件，越来越多的证据表明IDH突变与肿瘤的代谢重编程有关。胆固醇代谢失调是肿瘤细胞的一个标志，但IDH突变的胶质瘤中的胆固醇稳态仍不清楚。在本研究中，我们发现星形胶质细胞特异性突变体IDH1(R132H)敲打蛋白降低了小鼠脑中的胆固醇含量，并破坏了髓鞘的结构。在U87和U251细胞中，突变IDH1的表达持续降低胆固醇水平。此外，我们还发现IDH1突变增加了24(S)-羟基胆固醇(24-OHC)的产生，24-OHC不仅是胆固醇清除的代谢物，而且还作为肝脏X受体(LXRs)的内源性配体发挥作用。在IDH1突变的胶质瘤细胞中，升高的24-OHC激活LXRs，从而通过上调低密度脂蛋白受体(LDLR)的可诱导降解物(IDOL)来加速LDLR的降解。低密度脂蛋白受体在IDH1突变胶质瘤细胞中的表达减少，从而减少了低密度脂蛋白的摄取，从而减少了胆固醇的流入。此外，激活的LXRs还通过上调IDH1突变的星形胶质细胞和胶质瘤细胞中的ATP结合盒转运体A1(ABCA1)、Abcg1和载脂蛋白E(ApoE)来促进胆固醇外流。作为反馈，胆固醇水平的降低刺激了胆固醇的生物合成，这使得IDH1突变的胶质瘤细胞对阿托伐他汀更敏感，阿托伐他汀是3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂。突变的IDH调节的胆固醇稳态的改变为IDH突变的胶质瘤提供了一个关键的治疗策略。
Isocitrate dehydrogenase (IDH) mutation is the most important initiating event in gliomagenesis, and the increasing evidence shows that IDH mutation is associated with the metabolic reprogramming in the tumor. Dysregulated cholesterol metabolism is a hallmark of tumor cells, but the cholesterol homeostasis in IDH-mutated glioma is still unknown. In this study, we found that astrocyte-specific mutant IDH1(R132H) knockin reduced the cholesterol contents and damaged the structure of myelin in mouse brains. In U87 and U251 cells, the expression of mutant IDH1 consistently reduced the cholesterol levels. Furthermore, we found that IDH1 mutation enhanced the production of 24(S)-hydroxycholesterol (24-OHC), which is not only the metabolite of cholesterol elimination, but also functions as an endogenous ligand for the liver X receptors (LXRs). In IDH1-mutant glioma cells, the elevated 24-OHC activated LXRs, which consequently accelerated the low-density lipoprotein receptor (LDLR) degradation by upregulating the inducible degrader of the LDLR (IDOL). The reduced LDLR expressions in IDH1-mutant glioma cells abated the uptakes of low-density lipoprotein (LDL) to decrease the cholesterol influx. In addition, the activated LXRs also promoted the cholesterol efflux by elevating the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in both IDH1-mutant astrocytes and glioma cells. As a feedback, the reduced cholesterol levels stimulated the cholesterol biosynthesis, which made IDH1-mutated glioma cells more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. The altered cholesterol homeostasis regulated by mutant IDH provides a pivotal therapeutical strategy for the IDH-mutated gliomas.
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DOI：
10.1073/pnas.96.13.7238
发表时间：
1999-06-22
影响因子：
11.1
作者：
Lund, EG;Guileyardo, JM;Russell, DW
通讯作者：
Russell, DW
DOI：
10.1126/science.1168974
发表时间：
2009-07-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zelcer N;Hong C;Boyadjian R;Tontonoz P
通讯作者：
Tontonoz P
Perilipin 5 减轻 HCV NS5A 诱导的肝脏脂毒性损伤
影响因子：
4.5
作者：
Zhang Jin;Gao Xing;Yuan Yuan;Sun Chao;Zhao Yuanlin;Xiao Liming;Yang Ying;Gu Yu;Yang Risheng;Hu Peizhen;Zhang Lijun;Wang Chao;Ye Jing
通讯作者：
Ye Jing
影响因子：
4.7
作者：
Fujiyoshi, Masachika;Ohtsuki, Sumio;Terasaki, Tetsuya
通讯作者：
Terasaki, Tetsuya
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.