Open AccessNetwork analyses identify liver‐specific targets for treating liver diseases
Author(s) -
Lee Sunjae,
Zhang Cheng,
Liu Zhengtao,
Klevstig Martina,
Mukhopadhyay Bani,
Bergentall Mattias,
Cinar Resat,
Ståhlman Marcus,
Sikanic Natasha,
Park Joshua K,
Deshmukh Sumit,
Harzandi Azadeh M,
Kuijpers Tim,
Grøtli Morten,
Elsässer Simon J,
Piening Brian D,
Snyder Michael,
Smith Ulf,
Nielsen Jens,
Bäckhed Fredrik,
Kunos George,
Uhlen Mathias,
Boren Jan,
Mardinoglu Adil
Publication year - 2017
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20177703
Subject(s) - biology , kexin , lipogenesis , nonalcoholic fatty liver disease , fatty liver , fatty acid synthase , hepatocellular carcinoma , pcsk9 , proprotein convertase , liver cancer , liver disease , cancer research , gene , endocrinology , biochemistry , medicine , disease , cholesterol , ldl receptor , lipoprotein
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 ( CN s) 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 ( PNPLA 3), and proprotein convertase subtilisin/kexin type 9 ( PCSK 9), all of which are potential targets for drug development.