LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice
LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice
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DOI：
10.1021/acs.jmedchem.1c00175
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发表时间：
2021-07-12
影响因子：
7.3
通讯作者：
Tang, Lan
中科院分区：
文献类型：
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作者：
Liang, Zhi;Chen, Yulian;Tang, Lan
抗肾细胞癌药物piericidin A（PA）和glucopiericidin A（GPA）是两种抗肾细胞癌候选药物，对肾癌移植瘤小鼠具有肝毒性。蛋白质组学和转录组学揭示了与胆固醇处置相关的肝毒性，因为RCC的特征是胆固醇积聚。PA/GPA在高胆固醇饮食（HCD）喂养的小鼠中加重肝毒性，而在普通饮食喂养的小鼠中不表现出毒性。肝内胆固醇高蓄积是肝X受体（LXR）介导的细胞色素P450家族7亚家族A成员1（CYP 7A 1）的抑制和低密度脂蛋白受体（LDLR）的激活。法尼醇X核受体（FXR）也被下调的靶基因OST α抑制。与PA直接与LXR α结合作为抑制剂不同，GPA在肝脏中作为前药存在，并由于转化为PA而发挥毒性作用。表面等离子体共振（SPR）和对接结果的17 piericidins说明糖苷发挥没有LXR α结合活性。GPA治疗小鼠的较长存活时间表明，抗RCC药物研究的进一步探索应集中在减少糖苷转化为PA并集中在肾脏肿瘤而不是肝脏中以降低肝毒性的风险。
Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OST alpha. Different from PA directly combined with LXR alpha as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXR alpha binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.