En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.
En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.
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DOI：
10.1016/j.cell.2022.09.031
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发表时间：
2022-10-27
期刊：
影响因子：
64.5
通讯作者：
Takebe, Takanori
中科院分区：
文献类型：
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作者：
Kimura, Masaki;Iguchi, Takuma;Iwasawa, Kentaro;Dunn, Andrew;Thompson, Wendy L.;Yoneyama, Yosuke;Chaturvedi, Praneet;Zone, Aaron M.;Wintzinger, Michelle;Quattorcelli, Matti;Watanabe-Chailland, Miki;Zhu, Gaohui;Fujimoto, Masanobu;Kumbaji, Meenasri;Kodaka, Asuka;Gindin, Yevgeniy;Chung, Chuhan;Myers, Robert P.;Subramanian, G. Mani;Hwa, Vivian;Takebe, Takanori
常见疾病的基因型-表型关联常因多效性和代谢状态而复杂化。在这里，我们设计了一个合并的人类脂肪性肝炎类器官面板，以研究代谢状态对基因型-表型关联的影响。胰岛素不敏感条件下的大规模人群表型分析预测了关键的非酒精性脂肪性肝炎（NASH）遗传因素，包括葡萄糖激酶调节蛋白(GCKR)-rs1260326:C>T。NASH临床队列分析显示，GCKR-rs1260326-T等位基因仅在糖尿病状态下升高疾病严重程度，但在非糖尿病状态下可防止纤维化。转录组学、代谢组学和药理学分析表明，GCKR-rs1260326引起了显著的线粒体功能障碍，二甲双胍不能逆转这种功能。解偶联氧化机制减轻了线粒体功能障碍，允许适应增加的脂肪酸供应，同时防止氧化应激，为未来糖尿病性NASH的治疗方法奠定了基础。因此，培养皿中基因型-表型关联策略解开了代谢相关基因变异功能的对立作用，并为精确肝病学提供了丰富的机制、诊断和治疗推断工具箱。人类类器官建模结合基因型-表型关联研究解开了脂肪性肝炎易感基因变异的独特对立作用
Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, in-a-dish genotype-phenotype association strategies disentangled the opposing roles of metabolic-associated gene variant functions, and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. Human organoid modeling combined with genotype-phenotype association studies disentangles the unique opposing roles of a steatohepatitis susceptible gene variant
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影响因子：
5.8
作者：
Kimura M;Azuma M;Zhang RR;Thompson W;Mayhew CN;Takebe T
通讯作者：
Takebe T
DOI：
10.1161/circgenetics.109.914267
发表时间：
2010-08
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Keebler ME;Deo RC;Surti A;Konieczkowski D;Guiducci C;Burtt N;Buxbaum SG;Sarpong DF;Steffes MW;Wilson JG;Taylor HA;Kathiresan S
通讯作者：
Kathiresan S
影响因子：
3.7
作者：
Kendig, Katherine, I;Baheti, Saurabh;Mainzer, Liudmila S.
通讯作者：
Mainzer, Liudmila S.
影响因子：
--
作者：
Belalcazar, L. Maria;Papandonatos, George D.;Huggins, Gordon S.
通讯作者：
Huggins, Gordon S.
影响因子：
30.8
作者：
通讯作者：
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