A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.
A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.
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DOI：
10.1038/s42003-023-04739-9
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发表时间：
2023-04-24
影响因子：
5.9
通讯作者：
Duncan, Stephen A. A.
中科院分区：
文献类型：
--
作者：
Liu, Jui-Tung;Doueiry, Caren;Jiang, Yu-lin;Blaszkiewicz, Josef;Lamprecht, Mary Paige;Heslop, James A. A.;Peterson, Yuri K. K.;Carten, Juliana Debrito;Traktman, Paula;Yuan, Yang;Khetani, Salman R. R.;Twal, Waleed O. O.;Duncan, Stephen A. A.
家族性高胆固醇血症（FH）患者患有过高水平的低密度脂蛋白胆固醇（LDL-C），其可引起严重的心血管疾病。他汀类药物、胆汁酸螯合剂、PCSK 9抑制剂和胆固醇吸收抑制剂在治疗具有纯合LDLR基因突变（hoFH）的FH患者时均无效。批准用于hoFH治疗的药物通过调节稳态载脂蛋白B（apo B）水平来控制脂蛋白的产生。不幸的是，这些药物具有副作用，包括肝甘油三酯的积累、肝脂肪变性和肝酶水平升高。为了鉴定更安全的化合物，我们使用iPSC衍生的肝细胞平台从130，000种化合物的专有库中筛选了一组具有结构代表性的10，000种小分子。筛选揭示了可以减少小鼠培养肝细胞和人源化肝脏中apoB分泌的分子。这些小分子非常有效，不会引起异常的脂质积聚，并且具有与任何已知的降胆固醇药物不同的化学结构。iPSC衍生的肝细胞用于鉴定肝脏分泌apoB而不引起脂肪变性的小分子抑制剂。
Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not cause abnormal lipid accumulation, and share a chemical structure that is distinct from any known cholesterol lowering drug. iPSC-derived hepatocytes are used to identify small molecule inhibitors of apoB secretion by the liver without causing steatosis.
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影响因子：
20.1
作者：
Amengual J;Guo L;Strong A;Madrigal-Matute J;Wang H;Kaushik S;Brodsky JL;Rader DJ;Cuervo AM;Fisher EA
通讯作者：
Fisher EA
影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
4.8
作者：
Fisher, EA;Pan, M;Williams, KJ
通讯作者：
Williams, KJ
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V