小柯机器人

德国环境健康研究中心Stephan Herzig、Anne Loft研究团队取得进展。他们发现肝脏纤维化激活的转录网络控制肝细胞重编程和细胞间通讯。相关论文于2021年7月7日发表于《细胞—代谢》杂志。

使用细胞类型解析基因组学，研究人员发现在非酒精性脂肪肝炎 (NASH)进展过程中，肝细胞基因组和转录的全面改变导致肝细胞特性丧失。肝细胞重编程受到纤维化激活转录因子网络的密切调控，例如转录因子Elf-3 (ELF3)和锌指蛋白GLIS2 (GLIS2)。其次，由ELF3和GLIS2 控制的纤维化依赖性肝因子基因靶向与疾病相关肝星状细胞的基因程序。

因此，相互关联的转录因子网络不仅导致了肝细胞功能障碍，而且还产生了NASH和纤维化进展所需的肝内环境，这意味着靶向分子“以中心为中心”的策略优于目前单靶点的NASH治疗方法。

据介绍，肝纤维化是代谢相关脂肪肝患者长期死亡率的有效预测指标；然而，从相对良性的脂肪肝发展为晚期非酒精性脂肪肝 (NASH) 和肝纤维化的机制尚不完全清楚。

附：英文原文

Title: Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Author: Anne Loft, Ana Jimena Alfaro, Sren Fisker Schmidt, Felix Boel Pedersen, Mike Krogh Terkelsen, Michele Puglia, Kan Kau Chow, Annette Feuchtinger, Maria Troullinaki, Adriano Maida, Gretchen Wolff, Minako Sakurai, Riccardo Berutti, Bilgen Ekim üstünel, Peter Nawroth, Kim Ravnskjaer, Mauricio Berriel Diaz, Blagoy Blagoev, Stephan Herzig

Issue&Volume: 2021-07-07

Abstract: Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associatedfatty liver disease; yet, the mechanisms underlying the progression from the comparativelybenign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liverfibrosis are incompletely understood. Using cell-type-resolved genomics, we show thatcomprehensive alterations in hepatocyte genomic and transcriptional settings duringNASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogrammingwas under tight cooperative control of a network of fibrosis-activated transcriptionfactors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger proteinGLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genestargeting disease-associated hepatic stellate cell gene programs. Thus, interconnectedtranscription factor networks not only promoted hepatocyte dysfunction but also directedthe intra-hepatic crosstalk necessary for NASH and fibrosis progression, implyingthat molecular “hub-centered” targeting strategies are superior to existing mono-targetapproaches as currently used in NASH therapy.

DOI: 10.1016/j.cmet.2021.06.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00275-8

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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