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Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function

Journal article
Authors Z. T. Liu
C. Zhang
S. Lee
W. Kim
Martina Klevstig
A. M. Harzandi
N. Sikanic
M. Arif
Marcus Ståhlman
J. Nielsen
M. Uhlen
Jan Borén
A. Mardinoglu
Published in Metabolic Engineering
Volume 52
Pages 263-272
ISSN 1096-7176
Publication year 2019
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 263-272
Language en
Links dx.doi.org/10.1016/j.ymben.2019.01....
Keywords fatty liver-disease, analysis reveals, DNA-replication, database, association, stress, models, tools, risk, Biotechnology & Applied Microbiology
Subject categories Clinical Medicine

Abstract

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.

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