Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
Journal article, 2019
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of 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). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis. We found that modulation of these genes effects the total triglycerides levels within the cells and viability of the cells. Next, we generated IN for HepG2 cells, identified reporter transcription factors based on IN and found that the modulation of these genes affects key metabolic pathways associated with lipid metabolism (steroid biosynthesis, PPAR signalling pathway, fatty acid synthesis and oxidation) and cancer development (DNA replication, cell cycle and p53 signalling) involved in the progression of NAFLD and HCC. Finally, we observed that inhibition of PKLR lead to decreased glucose uptake and decreased mitochondrial activity in HepG2 cells. Hence, our systems level analysis indicated that PKLR can be targeted for development efficient treatment strategy for NAFLD and HCC.
Author
Zhengtao Liu
Royal Institute of Technology (KTH)
C. Zhang
Royal Institute of Technology (KTH)
Sunjae Lee
Royal Institute of Technology (KTH)
Woonghee Kim
Royal Institute of Technology (KTH)
M. Klevstig
Sahlgrenska University Hospital
Azadeh M. Harzandi
Royal Institute of Technology (KTH)
Natasha Sikanic
Royal Institute of Technology (KTH)
Muhammad Arif
Royal Institute of Technology (KTH)
Marcus Ståhlman
Sahlgrenska University Hospital
Jens Christian Froslev Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Mathias Uhlen
Royal Institute of Technology (KTH)
Jan Borén
Sahlgrenska University Hospital
Adil Mardinoglu
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
King's College London
Royal Institute of Technology (KTH)
Metabolic Engineering
1096-7176 (ISSN) 1096-7184 (eISSN)
Vol. 52 263-272Subject Categories
Cell Biology
Cell and Molecular Biology
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
DOI
10.1016/j.ymben.2019.01.001
PubMed
30615941