小柯机器人

美国辛辛那提儿童医院医疗中心Takanori Takebe研究组发现，大量的类器官表型为NASH的代谢相关遗传易感性提供信息。该研究于2022年10月13日在线发表于国际一流学术期刊《细胞》。

研究人员设计了一个集合的人类脂肪性肝炎的类器官群体，来研究代谢状态对基因型-表型关联的影响。在胰岛素不敏感的条件下，基于人群的表型分析预测了关键的非酒精性脂肪性肝炎（NASH）的遗传因素，包括葡萄糖激酶调节蛋白（GCKR）-rs1260326:C>T。对NASH临床队列的分析显示，GCKR-rs1260326-T等位基因仅在糖尿病状态下提高疾病的严重程度，但在非糖尿病状态下保护纤维化。

转录组、代谢组和药理学分析表明，GCKR-rs1260326导致了明显的线粒体功能障碍，并且二甲双胍不能逆转这种障碍。解除氧化机制减轻了线粒体功能障碍，并允许适应脂肪酸供应的增加，同时保护其免受氧化应激，为未来治疗糖尿病NASH的方法奠定了基础。因此，“in-a-dish”的基因型-表型关联策略分解了代谢相关基因变异功能的对立作用，并为精准肝病学提供了丰富的机制、诊断和治疗推理工具箱。

据悉，常见疾病的基因型-表型关联往往因多态性和代谢状态而变得复杂。

附：英文原文

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

Author: Masaki Kimura, Takuma Iguchi, Kentaro Iwasawa, Andrew Dunn, Wendy L. Thompson, Yosuke Yoneyama, Praneet Chaturvedi, Aaron M. Zorn, Michelle Wintzinger, Mattia Quattrocelli, Miki Watanabe-Chailland, Gaohui Zhu, Masanobu Fujimoto, Meenasri Kumbaji, Asuka Kodaka, Yevgeniy Gindin, Chuhan Chung, Robert P. Myers, G. Mani Subramanian, Vivian Hwa, Takanori Takebe

Issue&Volume: 2022-10-13

Abstract: Genotype-phenotype associations for common diseases are often compounded by pleiotropyand metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitisto investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predictedkey non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinaseregulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protectsfrom fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacologicalanalyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanismsmitigated mitochondrial dysfunction and permitted adaptation to increased fatty acidsupply while protecting against oxidant stress, forming a basis for future therapeuticapproaches for diabetic NASH. Thus, “in-a-dish” genotype-phenotype association strategies disentangle the opposing roles of metabolic-associatedgene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inferencetoolbox toward precision hepatology.

DOI: 10.1016/j.cell.2022.09.031

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01250-8