美国德克萨斯大学西南医学中心Hao Zhu课题组在研究中取得进展。他们探明了肝硬化内的PKD1突变克隆抑制脂肪性肝炎而不促进癌症。这一研究成果发表在2024年6月19日出版的国际学术期刊《细胞—代谢》上。

来自30名慢性肝病患者的150个肝脏样本的超深度靶向测序显示复发性体细胞突变。PKD1突变在30%的患者中被观察到，而仅在1.3%的肝细胞癌(HCCs)中被检测到。为了探究肿瘤抑制因子的功能，该课题组在两个肝细胞癌细胞系和六个体内模型中干扰PKD1，在一些情况下显示PKD1丢失可以预防肝细胞癌，但在大多数情况下没有影响。

然而，Pkd1单倍体功能不全加速了部分肝切除术后的再生。研究组在脂肪肝疾病中检测了Pkd1，发现Pkd1缺失对脂肪变性和葡萄糖耐受不良具有保护作用。在机制上，Pkd1缺失选择性地增加了mTOR信号，而没有SREBP-1c激活。总之，PKD1突变在器官水平上发挥适应性功能而不增加转化风险。

据介绍，选择非恶性组织中的体细胞突变是因为它们赋予了更高的克隆适应度。然而，尚不确定这些克隆是否有益于器官健康。

附：英文原文

Title: PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer

Author: Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P. Wallace, Alan S.L. Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G. Singal, Adam Yopp, Tao Wang, Hao Zhu

Issue&Volume: 2024-06-19

Abstract: Somatic mutations in non-malignant tissues are selected for because they confer increasedclonal fitness. However, it is uncertain whether these clones can benefit organ health.Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver diseasepatients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3%of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality,we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We testedPkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary,PKD1 mutations exert adaptive functionality on the organ level without increasing transformationrisk.

DOI: 10.1016/j.cmet.2024.05.015

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00191-8