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

Cell. 2022 Oct 27;185(22):4216-4232.e16. doi: 10.1016/j.cell.2022.09.031. Epub 2022 Oct 13.

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.

Keywords: GCKR-rs1260326; NASH; de novo lipogenesis; genotype-phenotype association; human liver organoid; iPSC; mitochondrial dysfunction; population organoid panel.

Publication types

  • Video-Audio Media
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Liver
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Organoids