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
17444292 (eISSN)
Vol. 13 8 938Ämneskategorier
Cellbiologi
DOI
10.15252/msb.20177703