Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.
Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.
复制标题
鉴定侧链氧化甾醇为新的肝X受体激动剂，在治疗心血管和神经退行性疾病方面具有治疗潜力。
DOI：
10.3390/ijms24021290
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发表时间：
2023-01-09
影响因子：
5.6
通讯作者：
Mulder, Monique T.
中科院分区：
文献类型：
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作者：
Zhan, Na;Wang, Boyang;Martens, Nikita;Liu, Yankai;Zhao, Shangge;Voortman, Gardi;Van Rooij, Jeroen;Leijten, Frank;Vanmierlo, Tim;Kuipers, Folkert;Jonker, Johan W.;Bloks, Vincent W.;Luetjohann, Dieter;Palumbo, Marcella;Zimetti, Francesca;Adorni, Maria Pia;Liu, Hongbing;Mulder, Monique T.
核受体-肝X受体(LXR、α和β)是心血管和神经退行性疾病的潜在治疗靶点，因为它们在调节脂质平衡和炎症过程中起着关键作用。特定的氧(植物)甾醇以不同的方式调节LXRs的转录活性，为开发具有改进的治疗特性的化合物提供了机会。我们从羊栖菜中分离得到氧合植物甾醇，并合成了侧链氧化甾醇衍生物。在荧光素酶报告分析和诱导参与细胞胆固醇转换的LXR靶基因APOE、ABCA1和Abcg1中，有五个24-氧化的甾醇对LXRα/β的激活表现出很高的效力：3-β-羟基-5-烯-24-酸甲酯(S1)、甲基(3-β)-3-醛-脱氧醇-5-烯-24-酸(S2)、24-酮胆固醇(S6)、(3-β，22E)-3-羟基-5，22-二烯-24-酮(N10)和岩藻甾醇-24，28环氧化物(N12)。这些化合物在HepG2细胞或星形细胞瘤细胞中诱导SREBF1，但不能诱导SREBP1c介导的成脂基因，如SCD1、ACACA和FASN。此外，S2和S6还促进了HepG2细胞的胆固醇外流。5种氧化甾醇均通过上调细胞色素P4 6A1，编码胆固醇转化为2 4(S)-羟基胆固醇的酶，诱导内源性LXR激动剂2 4(S)-羟基胆固醇的产生；S1和S6也可能通过上调桥粒甾醇的产生而起作用。因此，我们确定了五种新的激活LXR的24-氧化甾醇，它们具有治疗神经退行性疾病和心血管疾病的潜力。
The nuclear receptors—liver X receptors (LXR α and β) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/β activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3β-hydroxychol-5-en-24-oate (S1), methyl (3β)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3β,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.
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DOI：
10.1002/ar.a.20015
发表时间：
2004-04-01
期刊：
ANATOMICAL RECORD PART A-DISCOVERIES IN MOLECULAR CELLULAR AND EVOLUTIONARY BIOLOGY
影响因子：
--
作者：
Annicotte, JS;Schoonjans, K;Auwerx, J
通讯作者：
Auwerx, J
影响因子：
14.5
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
通讯作者：
Cartier, Nathalie
影响因子：
6.1
作者：
Chen, Zhen;Liu, Jiao;Liu, Hongbing
通讯作者：
Liu, Hongbing
影响因子：
2.7
作者：
Iida, T;Kakiyama, G;Hofmann, AF
通讯作者：
Hofmann, AF
影响因子：
3.8
作者：
Feng, Mei-Tang;Wang, Ting;Mao, Shui-Chun
通讯作者：
Mao, Shui-Chun