生物
脂肪性肝炎
表型
葡萄糖激酶
代谢组学
脂肪肝
多效性
遗传学
脂毒性
基因型
人口
生物信息学
疾病
基因
内科学
胰岛素
内分泌学
胰岛素抵抗
医学
环境卫生
作者
Masaki Kimura,Takuma Iguchi,Kentaro Iwasawa,Andrew Dunn,Wendy L. Thompson,Yoshimasa Yoneyama,Praneet Chaturvedi,Aaron M. Zorn,Michelle Wintzinger,Mattia Quattrocelli,Miki Watanabe-Chailland,Guoqiang Zhu,Masanobu Fujimoto,Meenasri Kumbaji,Asuka Kodaka,Yevgeniy Gindin,Chuhan Chung,Robert P. Myers,G. Mani Subramanian,Vivian Hwa,Takanori Takebe
出处
期刊:Cell
[Elsevier]
日期:2022-10-01
卷期号:185 (22): 4216-4232.e16
被引量:25
标识
DOI:10.1016/j.cell.2022.09.031
摘要
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 disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
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