Network analyses identify liver-specific targets for treating liver diseases
Journal article, 2017

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.

metabolism

NAFLD

co-regulation

co-expression

HCC

Author

SangWook Lee

Royal Institute of Technology (KTH)

C. Zhang

Royal Institute of Technology (KTH)

Z. T. Liu

Royal Institute of Technology (KTH)

M. Klevstig

Sahlgrenska University Hospital

B. Mukhopadhyay

National Institute on Alcohol Abuse and Alcoholism

Mattias Bergentall

Sahlgrenska University Hospital

R. Cinar

National Institute on Alcohol Abuse and Alcoholism

Marcus Ståhlman

Sahlgrenska University Hospital

Natasha Sikanic

Royal Institute of Technology (KTH)

Joshua K. Park

National Institute on Alcohol Abuse and Alcoholism

Sumit Deshmukh

Royal Institute of Technology (KTH)

Azadeh M. Harzandi

Royal Institute of Technology (KTH)

Tim Kuijpers

Royal Institute of Technology (KTH)

Morten Grötli

University of Gothenburg

Simon J. Elsässer

Karolinska Institutet

B. D. Piening

Stanford University

M. Snyder

Stanford University

U. Smith

Sahlgrenska University Hospital

Jens B Nielsen

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Fredrik Bäckhed

Sahlgrenska University Hospital

G. Kunos

National Institute on Alcohol Abuse and Alcoholism

Mathias Uhlen

Royal Institute of Technology (KTH)

Jan Borén

Sahlgrenska University Hospital

Adil Mardinoglu

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 13 8 938

Subject Categories

Cell Biology

DOI

10.15252/msb.20177703

More information

Latest update

4/18/2018