Network analyses identify liver-specific targets for treating liver diseases.
Network analyses identify liver-specific targets for treating liver diseases.
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网络分析确定用于治疗肝病的肝特异性靶标。
DOI：
10.15252/msb.20177703
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发表时间：
2017-08-21
影响因子：
9.9
通讯作者：
Mardinoglu A
中科院分区：
文献类型：
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作者：
Lee S;Zhang C;Liu Z;Klevstig M;Mukhopadhyay B;Bergentall M;Cinar R;Ståhlman M;Sikanic N;Park JK;Deshmukh S;Harzandi AM;Kuijpers T;Grøtli M;Elsässer SJ;Piening BD;Snyder M;Smith U;Nielsen J;Bäckhed F;Kunos G;Uhlen M;Boren J;Mardinoglu A
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。我们首先生成了46个人类组织和肝癌的共表达网络（CNs），以探索基因之间的功能关系，并检查了功能和物理相互作用之间的重叠。由于新生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，我们研究了与脂肪酸合成酶（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的表达。人类癌细胞系、小鼠肝脏样本和原代人肝细胞的实验证实了我们的预测，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，我们确定了与NAFLD发病机制相关的肝脏特异性基因，如丙酮酸激酶肝和红细胞（PKLR），或与HCC发病机制相关的肝脏特异性基因，如PKLR， patatin样磷脂酶结构域3 （PNPLA3）和蛋白转化酶枯草杆菌素/kexin 9型（PCSK9），所有这些都是药物开发的潜在靶点。
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.
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影响因子：
16.6
作者：
Hyötyläinen T;Jerby L;Petäjä EM;Mattila I;Jäntti S;Auvinen P;Gastaldelli A;Yki-Järvinen H;Ruppin E;Orešič M
通讯作者：
Orešič M
影响因子：
9.9
作者：
Mardinoglu A;Bjornson E;Zhang C;Klevstig M;Söderlund S;Ståhlman M;Adiels M;Hakkarainen A;Lundbom N;Kilicarslan M;Hallström BM;Lundbom J;Vergès B;Barrett PH;Watts GF;Serlie MJ;Nielsen J;Uhlén M;Smith U;Marschall HU;Taskinen MR;Boren J
通讯作者：
Boren J
影响因子：
8.8
作者：
Bjornson, Elias;Mukhopadhyay, Bani;Mardinoglu, Adil
通讯作者：
Mardinoglu, Adil
影响因子：
29
作者：
Jeong, Won-il;Osei-Hyiaman, Douglas;Kunos, George
通讯作者：
Kunos, George
影响因子：
--
作者：
Kew, M. C.
通讯作者：
Kew, M. C.