Match!

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

Published on Mar 1, 2019in Metabolic Engineering7.808
· DOI :10.1016/J.YMBEN.2019.01.001
Zhengtao Liu7
Estimated H-index: 7
(KTH: Royal Institute of Technology),
Cheng Zhang33
Estimated H-index: 33
(KTH: Royal Institute of Technology)
+ 10 AuthorsAdil Mardinoglu31
Estimated H-index: 31
(Chalmers University of Technology)
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.
  • References (60)
  • Citations (6)
📖 Papers frequently viewed together
37 Citations
2 Citations
1 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References60
Newest
#1Montgomery Blencowe (UCLA: University of California, Los Angeles)H-Index: 4
#2Tilan Karunanayake (UCLA: University of California, Los Angeles)H-Index: 1
Last. Xia Yang (UCLA: University of California, Los Angeles)H-Index: 34
view all 5 authors...
Non-alcoholic fatty liver disease (NAFLD) is a progressive condition of the liver encompassing a range of pathologies including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Research into this disease is imperative due to its rapid growth in prevalence, economic burden, and current lack of FDA approved therapies. NAFLD involves a highly complex etiology that calls for multi-tissue multi-omics network approaches to uncover the pathogenic genes and proce...
10 CitationsSource
#1Carlos A. Aguilar-Salinas (Tec: Monterrey Institute of Technology and Higher Education)H-Index: 9
#2Tannia Viveros-Ruiz (UNAM: National Autonomous University of Mexico)H-Index: 3
The metabolic syndrome (MetS) concept gathers in a single entity a set of metabolic abnormalities that have in common a close relationship with ectopic deposit of lipids, insulin resistance, and chronic low-grade inflammation. It is a valuable teaching tool to help health professionals to understand and integrate the consequences of lipotoxicity and the adverse metabolic consequences of insulin resistance. Also, it is useful to identify subjects with a high risk for having incident type 2 diabet...
8 CitationsSource
#1Adil Mardinoglu (Chalmers University of Technology)H-Index: 31
#2Jan Borén (Sahlgrenska University Hospital)H-Index: 67
Last. Jens Brehm Nielsen (Chalmers University of Technology)H-Index: 4
view all 5 authors...
Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein–protein interaction, signalling and co-expression networks, can provi...
32 CitationsSource
#1Adil Mardinoglu (Chalmers University of Technology)H-Index: 31
#2Hao Wu (Sahlgrenska University Hospital)H-Index: 11
Last. Jan Borén (Sahlgrenska University Hospital)H-Index: 67
view all 29 authors...
A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Her ...
84 CitationsSource
#1Adil Mardinoglu (Chalmers University of Technology)H-Index: 31
#2Mathias Uhlén (KTH: Royal Institute of Technology)H-Index: 103
Last. Jan Borén (Sahlgrenska University Hospital)H-Index: 67
view all 3 authors...
Multi-omics multi-tissue data are used to interpret genome-wide association study results from mice to identify key driver genes of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat (steatosis) in the liver due to causes other than excessive alcohol consumption. The disease may progress to more severe forms of liver diseases, including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. In this issue of Cell Systems , Kris...
5 CitationsSource
#1Karthickeyan Chella Krishnan (UCLA: University of California, Los Angeles)H-Index: 8
#2Zeyneb Kurt (UCLA: University of California, Los Angeles)H-Index: 9
Last. Xia Yang (UCLA: University of California, Los Angeles)H-Index: 34
view all 20 authors...
Summary The etiology of non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is poorly understood. To understand the causal mechanisms underlying NAFLD, we conducted a multi-omics, multi-tissue integrative study using the Hybrid Mouse Diversity Panel, consisting of ∼100 strains of mice with various degrees of NAFLD. We identified both tissue-specific biological processes and processes that were shared between adipose and liver tissues. We then used gene netwo...
36 CitationsSource
#1Sunjae Lee (KTH: Royal Institute of Technology)H-Index: 14
#2Cheng Zhang (KTH: Royal Institute of Technology)H-Index: 33
Last. Adil Mardinoglu (Chalmers University of Technology)H-Index: 31
view all 13 authors...
Biological networks provide new opportunities for understanding the cellular biology in both health and disease states. We generated tissue specific integrated networks (INs) for liver, muscle and adipose tissues by integrating metabolic, regulatory and protein-protein interaction networks. We also generated human co-expression networks (CNs) for 46 normal tissues and 17 cancers to explore the functional relationships between genes as well as their relationships with biological functions, and in...
18 CitationsSource
#1Ivan V. Kulakovskiy (EIMB: Engelhardt Institute of Molecular Biology)H-Index: 17
#2Ilya E. Vorontsov (RAS: Russian Academy of Sciences)H-Index: 9
Last. Vsevolod J. Makeev (EIMB: Engelhardt Institute of Molecular Biology)H-Index: 25
view all 12 authors...
: We present a major update of the HOCOMOCO collection that consists of patterns describing DNA binding specificities for human and mouse transcription factors. In this release, we profited from a nearly doubled volume of published in vivo experiments on transcription factor (TF) binding to expand the repertoire of binding models, replace low-quality models previously based on in vitro data only and cover more than a hundred TFs with previously unknown binding specificities. This was achieved by...
165 CitationsSource
#1Zobair M. Younossi (Inova Fairfax Hospital)H-Index: 73
#2Quentin M. Anstee (Newcastle University)H-Index: 46
Last. Elisabetta Bugianesi (UNITO: University of Turin)H-Index: 59
view all 8 authors...
NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.
683 CitationsSource
#1Mingtao Huang (Chalmers University of Technology)H-Index: 10
#2Jichen Bao (Chalmers University of Technology)H-Index: 5
Last. Jens NielsenH-Index: 125
view all 5 authors...
The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find tha...
22 CitationsSource
Cited By6
Newest
#1Mehmet Ozcan (Hacettepe University)H-Index: 1
#2Ozlem Altay (KTH: Royal Institute of Technology)H-Index: 2
Last. Adil Mardinoglu (KTH: Royal Institute of Technology)H-Index: 31
view all 9 authors...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death primarily due to the lack of effective targeted therapies. Despite the distinct morphological and phenotypic patterns of HCC, treatment strategies are restricted to relatively homogeneous therapies, including multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors. Therefore, more effective therapy options are needed to target dysregulated metabolic and molecular pathways in HCC. Integrative gen...
1 CitationsSource
#1Simon LamH-Index: 1
#2Stephen DoranH-Index: 1
Last. Adil MardinogluH-Index: 31
view all 9 authors...
The abnormalities in human metabolism have been implicated in the progression of several complex human diseases, including certain cancers. Hence, deciphering the underlying molecular mechanisms associated with metabolic reprogramming in a disease state can greatly assist in elucidating the disease aetiology. An invaluable tool for establishing connections between global metabolic reprogramming and disease development is the genome-scale metabolic model (GEM). Here, we review recent work on the ...
2 CitationsSource
#1Antonise M. Jaguezeski (UFSM: Universidade Federal de Santa Maria)H-Index: 5
#2Carine F. Souza (UFSM: Universidade Federal de Santa Maria)H-Index: 13
Last. Aleksandro Schafer da Silva (UFSM: Universidade Federal de Santa Maria)H-Index: 18
view all 10 authors...
Abstract Energy metabolism is a sensitive indicator of cellular disorders. Therefore, the objective of this study was to investigate changes in cardiac and hepatic energy metabolism during listeriosis using an experimental model. We divided gerbils into two groups: Control (n = 11) and orally Infected (n = 12) with 5 × 109 CFU/mL of Listeria monocytogenes. Euthanasia and sampling were performed on days 6 and 12 post-infection (PI). Histopathological lesions were not found in the heart; however, ...
Source
#1Montgomery Blencowe (UCLA: University of California, Los Angeles)H-Index: 4
#2Tilan Karunanayake (UCLA: University of California, Los Angeles)H-Index: 1
Last. Xia Yang (UCLA: University of California, Los Angeles)H-Index: 34
view all 5 authors...
Non-alcoholic fatty liver disease (NAFLD) is a progressive condition of the liver encompassing a range of pathologies including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Research into this disease is imperative due to its rapid growth in prevalence, economic burden, and current lack of FDA approved therapies. NAFLD involves a highly complex etiology that calls for multi-tissue multi-omics network approaches to uncover the pathogenic genes and proce...
10 CitationsSource
#1Cheng Zhang (KTH: Royal Institute of Technology)H-Index: 33
#1Cheng Zhang (KTH: Royal Institute of Technology)H-Index: 15
Last. Adil Mardinoglu (Chalmers University of Technology)H-Index: 31
view all 9 authors...
Relative Metabolic Differences version 2 (RMetD2) is a tool for integration of differentially expressed (DE) genes into genome-scale metabolic models (GEMs) for revealing the altered metabolism between two biological conditions. This method provides a robust evaluation of the metabolism by using flux ranges instead of a single set of flux distributions. RMetD2 classifies reactions into three different groups, namely up-regulated, down-regulated and unchanged, which enables systematic interpretat...
Source
#1Carlos A. Aguilar-Salinas (Tec: Monterrey Institute of Technology and Higher Education)H-Index: 9
#2Tannia Viveros-Ruiz (UNAM: National Autonomous University of Mexico)H-Index: 3
The metabolic syndrome (MetS) concept gathers in a single entity a set of metabolic abnormalities that have in common a close relationship with ectopic deposit of lipids, insulin resistance, and chronic low-grade inflammation. It is a valuable teaching tool to help health professionals to understand and integrate the consequences of lipotoxicity and the adverse metabolic consequences of insulin resistance. Also, it is useful to identify subjects with a high risk for having incident type 2 diabet...
8 CitationsSource