• En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.

En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.

Cell (2022-10-15)
Masaki Kimura, Takuma Iguchi, Kentaro Iwasawa, Andrew Dunn, Wendy L Thompson, Yosuke Yoneyama, Praneet Chaturvedi, Aaron M Zorn, Michelle Wintzinger, Mattia Quattrocelli, Miki Watanabe-Chailland, Gaohui Zhu, Masanobu Fujimoto, Meenasri Kumbaji, Asuka Kodaka, Yevgeniy Gindin, Chuhan Chung, Robert P Myers, G Mani Subramanian, Vivian Hwa, Takanori Takebe

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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Superoxide Dismutase, SOD, Activity Assay Kit, sufficient for 500 colorimetric tests