We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver-specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.

中文翻译：

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网络分析确定了治疗肝脏疾病的肝脏特异性靶点。


我们进行了综合网络分析，以确定可用于有效治疗肝脏疾病且副作用最小的靶点。我们首先为 46 个人体组织和肝癌生成共表达网络 (CN)，以探索基因之间的功能关系，并检查功能和物理相互作用之间的重叠。由于从头脂肪生成增加是非酒精性脂肪性肝病 (NAFLD) 和肝细胞癌 (HCC) 的一个特征，因此我们研究了与脂肪酸合酶 (FASN) 共表达的肝脏特异性基因。 CN 分析预测，抑制这些肝脏特异性基因会降低 FASN 表达。在人类癌细胞系、小鼠肝脏样本和原代人类肝细胞中进行的实验验证了我们的预测，证明了这些肝脏基因之间的功能关系，并表明它们的抑制会降低细胞生长和肝脏脂肪含量。总之，我们鉴定了与 NAFLD 发病机制相关的肝脏特异性基因，例如丙酮酸激酶肝脏和红细胞 (PKLR)，或与 HCC 发病机制相关的基因，例如 PKLR、patatin 样磷脂酶结构域 3 (PNPLA3) 和前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型（PCSK9），所有这些都是药物开发的潜在靶点。