Network analyses identify liver-specific targets for treating liver diseases
Artikel i vetenskaplig tidskrift, 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

Författare

SangWook Lee

Kungliga Tekniska Högskolan (KTH)

C. Zhang

Kungliga Tekniska Högskolan (KTH)

Z. T. Liu

Kungliga Tekniska Högskolan (KTH)

M. Klevstig

Sahlgrenska universitetssjukhuset

B. Mukhopadhyay

National Institute on Alcohol Abuse and Alcoholism

Mattias Bergentall

Sahlgrenska universitetssjukhuset

R. Cinar

National Institute on Alcohol Abuse and Alcoholism

Marcus Ståhlman

Sahlgrenska universitetssjukhuset

Natasha Sikanic

Kungliga Tekniska Högskolan (KTH)

Joshua K. Park

National Institute on Alcohol Abuse and Alcoholism

Sumit Deshmukh

Kungliga Tekniska Högskolan (KTH)

Azadeh M. Harzandi

Kungliga Tekniska Högskolan (KTH)

Tim Kuijpers

Kungliga Tekniska Högskolan (KTH)

Morten Grötli

Göteborgs universitet

Simon J. Elsässer

Karolinska Institutet

B. D. Piening

Stanford University

M. Snyder

Stanford University

U. Smith

Sahlgrenska universitetssjukhuset

Jens B Nielsen

Chalmers, Biologi och bioteknik, Systembiologi

Fredrik Bäckhed

Sahlgrenska universitetssjukhuset

G. Kunos

National Institute on Alcohol Abuse and Alcoholism

Mathias Uhlen

Kungliga Tekniska Högskolan (KTH)

Jan Borén

Sahlgrenska universitetssjukhuset

Adil Mardinoglu

Chalmers, Biologi och bioteknik, Systembiologi

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 13 938

Ämneskategorier

Cellbiologi

DOI

10.15252/msb.20177703