Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
Artikel i vetenskaplig tidskrift, 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.
Författare
Zhengtao Liu
Kungliga Tekniska Högskolan (KTH)
C. Zhang
Kungliga Tekniska Högskolan (KTH)
Sunjae Lee
Kungliga Tekniska Högskolan (KTH)
Woonghee Kim
Kungliga Tekniska Högskolan (KTH)
M. Klevstig
Sahlgrenska universitetssjukhuset
Azadeh M. Harzandi
Kungliga Tekniska Högskolan (KTH)
Natasha Sikanic
Kungliga Tekniska Högskolan (KTH)
Muhammad Arif
Kungliga Tekniska Högskolan (KTH)
Marcus Ståhlman
Sahlgrenska universitetssjukhuset
Jens Christian Froslev Nielsen
Chalmers, Biologi och bioteknik, Systembiologi
Mathias Uhlen
Kungliga Tekniska Högskolan (KTH)
Jan Borén
Sahlgrenska universitetssjukhuset
Adil Mardinoglu
Chalmers, Biologi och bioteknik, Systembiologi
King's College London
Kungliga Tekniska Högskolan (KTH)
Metabolic Engineering
1096-7176 (ISSN) 1096-7184 (eISSN)
Vol. 52 263-272Ämneskategorier
Cellbiologi
Cell- och molekylärbiologi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
DOI
10.1016/j.ymben.2019.01.001
PubMed
30615941