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• W4305013887 abstract "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 eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJiNDk3NGIwOGE2NDA0MzBiMjUzNjgxMjE0YWE5MWM4NCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjkxMjMzMjI0fQ.ArYm_C7j8vEJMee-2KKojfiLfrGPnmLpn6FFA2Eb4PamW3co9eI8UmGFesW-FK2oCZ07Yvw5mZZC7zxy91o3aQwPzrBKYKpzd_luW4mnJ7I7vP9zIjhMft1rv4MZfp_Inr84iUtFPdw-BPdSM3dWNfNnTet50wW060UG0SeYsmB579MXn040aPjCQQ2XuRe276lwbjYMI6H4EnXz40v3hGwBDc1-uUcvqwJiXjykqieUp_tKdZKbGmbd-lk96HQaJjm8rq1yR_avQWPdKaERVcO5ohWMwzm_OwkvqFIMyfSm4Iv12mfP4sbycrGD7tnvojWvKK-fsUua125dZxGwRQ (mp4, (4.73 MB) Download video" @default.
• W4305013887 created "2022-10-14" @default.
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• W4305013887 date "2022-10-01" @default.
• W4305013887 modified "2023-10-16" @default.
• W4305013887 title "En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH" @default.
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• W4305013887 doi "https://doi.org/10.1016/j.cell.2022.09.031" @default.
• W4305013887 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36240780" @default.

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