En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH
Summary
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. Copyright © 2022 Elsevier Inc. All rights reserved.
| Authors | Kimura M, Iguchi T, Iwasawa K, Dunn A, Thompson WL, Yoneyama Y, Chaturvedi P, Zorn AM, Wintzinger M, Quattrocelli M, Watanabe-Chailland M, Zhu G, Fujimoto M, Kumbaji M, Kodaka A, Gindin Y, Chung C, Myers RP, Subramanian GM, Hwa V, Takebe T |
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| Journal | Cell |
| Publication Date | 2022 Oct 27;185(22):4216-4232.e16 |
| PubMed | 36240780 |
| PubMed Central | PMC9617783 |
| DOI | 10.1016/j.cell.2022.09.031 |