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Network analyses identify liver-specific targets for treating liver diseases

Sunjae Lee1, Cheng Zhang1, Zhengtao Liu1

  • 1Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

Molecular Systems Biology
|August 23, 2017
PubMed

Insights

Researchers identified novel liver-specific genes, including PKLR, PNPLA3, and PCSK9, that are potential therapeutic targets for treating nonalcoholic fatty liver disease (NAFLD) and liver cancer (HCC) with minimal side effects.

Area of Science:

  • Genomics
  • Molecular Biology
  • Hepatology

Background:

  • Nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are characterized by increased *de novo* lipogenesis.
  • Identifying specific molecular targets is crucial for developing effective treatments with minimal side effects.

Purpose of the Study:

  • To identify liver-specific genes co-expressed with fatty acid synthase (FASN) using integrative network analyses.
  • To validate the functional roles of these genes in liver fat accumulation and cell growth.
  • To explore potential therapeutic targets for NAFLD and HCC.

Main Methods:

  • Generated co-expression networks (CNs) across 46 human tissues and liver cancer.
  • Examined overlap between functional and physical gene interactions.
  • Performed experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes.

Main Results:

  • CN analyses predicted that inhibiting specific liver genes decreases FASN expression.
  • Experimental validation confirmed functional relationships between identified liver genes.
  • Inhibition of these genes reduced cell growth and liver fat content in experimental models.

Conclusions:

  • Identified liver-specific genes, including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), are linked to NAFLD and HCC pathogenesis.
  • These genes represent promising targets for novel drug development for liver diseases.
Keywords:
HCCNAFLDco‐expressionco‐regulationmetabolism

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