期刊
CELL
卷 185, 期 22, 页码 4216-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2022.09.031
关键词
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资金
- Cincinnati Children's Reuter Foundation
- CURE
- NIH [DP2 DK128799-01, DK119982, DK121875, HL158531, DK130908, AG078174]
- CREST grant from Japan Agency for Medical Research and Development (AMED) [JP22gm1210012]
- Cincinnati Center for Autoimmune Liver Disease Fellowship Award
- PHS Grant of the Digestive Disease Research Core Center in Cincinnati [P30 DK078392]
- Falk Transformational Awards Pro-gram
- JST Moonshot RD Grant [JPMJMS2033, JPMJMS2022]
- Takeda Science Foundation
- Mitsubishi Foundation award
- AMED [JP20fk0210037, JP20bm0704025, JP21fk0210060, JP21bm0404045, JP22fk0210091, JP22fk0210106, JST JPJSBP220203101, JSPS JP18H02800]
- CCHMC grants
- CuSTOM pilot grant
The study found that the gene GCKR-rs1260326 has different effects on the disease under different metabolic states, providing new insights for future therapeutic approaches for diabetic NASH.
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 meta-bolic status on genotype-phenotype association. En masse population-based phenotypic analysis under in-sulin 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 mito-chondrial 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 dia-betic NASH. Thus, in-a-dishgenotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic infer-ence toolbox toward precision hepatology.
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