We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co‐expression networks (CNs) for ...46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver‐specific genes co‐expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver‐specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver‐specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin‐like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.
Synopsis
Integrative network analyses identify liver‐specific drug targets that can be used to effectively treat liver diseases including nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).
Co‐expression networks are generated for 46 human tissues and liver cancer.
Genes that are co‐expressed with fatty acid synthase (FASN) only in liver tissue are identified.
Inhibition of liver‐specific genes decreases liver fat and cell growth.
Liver‐specific genes can be targeted in order to treat NAFLD and HCC.
Integrative network analyses identify liver‐specific drug targets that can be used to effectively treat liver diseases including nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC).
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.
•We inhibited and overexpressed the liver-specific gene targets in HepG2 cells.•We generated HepG2 specific integrated networks for studying the global effect of gene modulation.•We found that the modulation of these genes affect key pathways associated with lipid metabolism and cancer development.•We identified a role of PKLR in limiting mitochondrial activity in the liver.
Fibrosis is the pathophysiological hallmark of progressive chronic kidney disease (CKD). The kidney is a highly metabolically active organ, and it has been suggested that disruption in its metabolism ...leads to renal fibrosis. We developed a longitudinal mouse model of acute kidney injury leading to CKD and an in vitro model of epithelial to mesenchymal transition to study changes in metabolism, inflammation, and fibrosis. Using transcriptomics, metabolic modeling, and serum metabolomics, we observed sustained fatty acid metabolic dysfunction in the mouse model from early to late stages of CKD. Increased fatty acid biosynthesis and downregulation of catabolic pathways for triglycerides and diacylglycerides were associated with a marked increase in these lipids in the serum. We therefore suggest that the kidney may be the source of the abnormal lipid profile seen in patients with CKD, which may provide insights into the association between CKD and cardiovascular disease.
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•Following AKI, markers of fibrosis and inflammation go up simultaneously•AKI is associated with reduced fatty acid oxidation and oxidative phosphorylation•Changes in metabolism persist as chronic kidney disease develops•Changes in metabolism are associated with increased serum levels of triglycerides
Human Metabolism; Systems Biology; Omics
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