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

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.

SUBMITTER: Kimura M

PROVIDER: S-EPMC9617783 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Kimura Masaki M Iguchi Takuma T Iwasawa Kentaro K Dunn Andrew A Thompson Wendy L WL Yoneyama Yosuke Y Chaturvedi Praneet P Zorn Aaron M AM Wintzinger Michelle M Quattrocelli Mattia M Watanabe-Chailland Miki M Zhu Gaohui G Fujimoto Masanobu M Kumbaji Meenasri M Kodaka Asuka A Gindin Yevgeniy Y Chung Chuhan C Myers Robert P RP Subramanian G Mani GM Hwa Vivian V Takebe Takanori T

Cell 20221013 22

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 co ...[more]

PMID: 36240780

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Project description:Background: Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutic agents such as doxorubicin, and contributes to development of heart failure. There is a pressing need for cardiac-specific therapeutics that prevent the cardiac complications of chemotherapy without compromising efficacy by directly targeting cardiomyocyte loss. Objectives: We employed massively parallel combinatorial genetic screening to search for miRNA combinations that promote cardiomyocyte survival. Methods: Combinatorial genetics en masse (CombiGEM) screening in a cardiomyocyte cell line was followed by validation studies in the original cell type as well as primary cardiomyocytes to search for miRNA combinations that promote survival under various stress conditions. The top candidate combination was tested human iPSC-derived cardiomyocyte and in vivo mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing and in silico miRNA target prediction provided insight into possible mechanisms. Results: CombiGEM screens and validation experiments identified multiple miRNA combinations that protected cardiomyocytes from doxorubicin in vitro. The most effective miRNA combination (miR-222 + miR-455) appeared to act synergistically and had protective effects in both murine and zebrafish in vivo doxorubicin cardiotoxicity models. RNA sequencing data revealed synergistic and additive regulation of mechanistically relevant genes and biological processes, including mitochondrial homeostasis, cellular respiration, DNA replication/damage response, oxidative and ER stress, angiogenesis, muscle contraction/relaxation, and others. Conclusions: We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. The results of this study further our knowledge of the cardiac effects of individual miRNAs and their combinations and demonstrate the value of the CombiGEM approach for discovery of cardioprotective combinatorial therapeutic candidates.

Dataset Information

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

Publications

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

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