한빛사논문
- 조회1,972
Sunjae Lee1,† , Cheng Zhang1,† , Zhengtao Liu1,†, Martina Klevstig2, Bani Mukhopadhyay3, Mattias Bergentall2, Resat Cinar3 , Marcus Ståhlman2, Natasha Sikanic1, Joshua K Park3, Sumit Deshmukh1, Azadeh M Harzandi1, Tim Kuijpers1, Morten Grøtli4, Simon J Elsässer5, Brian D Piening6, Michael Snyder6, Ulf Smith2, Jens Nielsen1,7 , Fredrik Bäckhed2, George Kunos3, Mathias Uhlen1 , Jan Boren2,* & Adil Mardinoglu1,7,**
1 Science for Life Laboratory, KTH – Royal Institute of Technology, Stockholm, Sweden
2 Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
3 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
4 Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
5 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
6 Department of Genetics, Stanford University, Stanford, CA, USA
7 Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
*Corresponding author.
**Corresponding author.
†These authors contributed equally to this work.
Abstract
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.
Keywords : co-expression; co-regulation; HCC; metabolism; NAFLD
논문정보
- Research article
- 2017년 08월 (BRIC 등록일 2017-08-29)
- 국외 연구진
- 의약학 > 인체시스템의학
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