Details

Autor(en) / Beteiligte

• Kimura, Masaki
• Iguchi, Takuma
• Iwasawa, Kentaro
• Dunn, Andrew
• Thompson, Wendy L.
• Yoneyama, Yosuke
• Chaturvedi, Praneet
• Zorn, Aaron M.
• Wintzinger, Michelle
• Quattrocelli, Mattia
• 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

Titel

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

Ist Teil von

• Cell, 2022-10, Vol.185 (22), p.4216-4232.e16

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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. [Display omitted] [Display omitted] •En masse liver organoid analysis informs NASH genotype-phenotype associations•Gene editing in organoids delineates GCKR-rs1260326 impact on glycolysis and lipogenesis•GCKR variant has opposing impacts on NASH severity with or without diabetes•Mitochondrial dysfunction is associated with GCKR variant-defined diabetic NASH Human organoid modeling combined with genotype-phenotype association studies disentangles the unique opposing roles of a steatohepatitis-susceptible gene variant.