Low‐density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia

Floeth, Matthias; Elges, Sandra; Gerß, Joachim; Schwöppe, Christian; Keßler, Torsten; Herold, Tobias; Wardelmann, Eva; Berdel, Wolfgang E.; Lenz, Georg; Mikesch, Jan‐Henrik; Hartmann, Wolfgang; Schliemann, Christoph; Angenendt, Linus

doi:10.1111/bjh.16853

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…Low-density apolipoprotein receptor (LDLR) is a mediator for cholesterol uptake in cells and is crucial for the clearance of cholesterol by the liver [ 77 ]. LDLR deficient rodents have been used to establish models of NAFLD [ 78 , 79 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis

et al. 2022

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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder. Defects in function/expression of genes/proteins are critical in initiation/progression of NAFLD. Natural products may modulate these genes/proteins. Curcumin improves steatosis, inflammation, and fibrosis progression. Here, bioinformatic tools, gene–drug and gene-disease databases were utilized to explore targets, interactions, and pathways through which curcumin could impact NAFLD. METHODS: Significant curcumin–protein interaction was identified (high-confidence:0.7) in the STITCH database. Identified proteins were investigated to determine association with NAFLD. gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed for significantly involved targets (p < 0.01). Specificity of obtained targets with NAFLD was estimated and investigated in Tissue/Cells–gene associations (PanglaoDB Augmented 2021, Mouse Gene Atlas) and Disease–gene association-based EnrichR algorithms (Jensen DISEASES, DisGeNET). RESULTS: Two collections were constructed: 227 protein–curcumin interactions and 95 NAFLD-associated genes. By Venn diagram, 14 significant targets were identified, and their biological pathways evaluated. Based on gene ontology, most targets involved stress and lipid metabolism. KEGG revealed chemical carcinogenesis, the AGE-RAGE signaling pathway in diabetic complications and NAFLD as the most common significant pathways. Specificity to diseases database (EnrichR algorithm) revealed specificity for steatosis/steatohepatitis. CONCLUSION: Curcumin may improve, or inhibit, progression of NAFLD through activation/inhibition of NAFLD-related genes.

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Section: Discussionmentioning

confidence: 99%

Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis

et al. 2022

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“…LDLR (low-density apolipoprotein receptor) is a mediator for cholesterol uptake in cells. It plays a crucial function in the clearance of cholesterol by the liver [ 119 ]. LDLR deficient rodents have been used to establish models of NAFLD [ 120 , 121 ].…”

Section: Discussionmentioning

confidence: 99%

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

Mahmoudi

Butler

Jamialahmadi

et al. 2021

BioMed Research International

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Background. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of liver damage, affecting ~25% of the global population. NAFLD comprises a spectrum of liver pathologies, from hepatic steatosis to nonalcoholic steatohepatitis (NASH), and may progress to liver fibrosis and cirrhosis. The presence of NAFLD correlates with metabolic disorders such as hyperlipidemia, obesity, blood hypertension, cardiovascular, and insulin resistance. Fenofibrate is an agonist drug for peroxisome proliferator-activated receptor alpha (PPARα), used principally for treatment of hyperlipidemia. However, fenofibrate has recently been investigated in clinical trials for treatment of other metabolic disorders such as diabetes, cardiovascular disease, and NAFLD. The evidence to date indicates that fenofibrate could improve NAFLD. While PPARα is considered to be the main target of fenofibrate, fenofibrate may exert its effect through impact on other genes and pathways thereby alleviating, and possibly reversing, NAFLD. In this study, using bioinformatics tools and gene-drug, gene-diseases databases, we sought to explore possible targets, interactions, and pathways involved in fenofibrate and NAFLD. Methods. We first determined significant protein interactions with fenofibrate in the STITCH database with high confidence (0.7). Next, we investigated the identified proteins on curated targets in two databases, including the DisGeNET and DISEASES databases, to determine their association with NAFLD. We finally constructed a Venn diagram for these two collections (curated genes-NAFLD and fenofibrate-STITCH) to uncover possible primary targets of fenofibrate. Then, Gene Ontology (GO) and KEGG were analyzed to detect the significantly involved targets in molecular function, biological process, cellular component, and biological pathways. A P value < 0.01 was considered the cut-off criterion. We also estimated the specificity of targets with NAFLD by investigating them in disease-gene associations (STRING) and EnrichR (DisGeNET). Finally, we verified our findings in the scientific literature. Results. We constructed two collections, one with 80 protein-drug interactions and the other with 95 genes associated with NAFLD. Using the Venn diagram, we identified 11 significant targets including LEP, SIRT1, ADIPOQ, PPARA, SREBF1, LDLR, GSTP1, VLDLR, SCARB1, MMP1, and APOC3 and then evaluated their biological pathways. Based on Gene Ontology, most of the targets are involved in lipid metabolism, and KEGG enrichment pathways showed the PPAR signaling pathway, AMPK signaling pathway, and NAFLD as the most significant pathways. The interrogation of those targets on authentic disease databases showed they were more specific to both steatosis and steatohepatitis liver injury than to any other diseases in these databases. Finally, we identified three significant genes, APOC3, PPARA, and SREBF1, that showed robust drug interaction with fenofibrate. Conclusion. Fenofibrate may exert its effect directly or indirectly, via modulation of several key targets and pathways, in the treatment of NAFLD.

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“…By screening clinical specimens and publicly available human datasets, highly expressed low-density lipoprotein (LDL) receptor (LDLR) in acute myeloid leukemia and breast cancer is associated with reduced recurrence-free survival, indicating LDLR is an independent adverse predictive marker [ 5 , 6 ]. Additionally, high mRNA levels of LDLR and LDLR related protein 1 (LRP1) are related to lower survival in pancreatic adenocarcinoma and worsened survival in bladder urothelial carcinoma patients, respectively [ 7 ].…”

Section: Lipid Metabolism Reprogramming As An Emerging Hallmark Of Ca...mentioning

confidence: 99%

New dawn for cancer cell death: Emerging role of lipid metabolism

Zhang¹,

Zhu²,

Li³

et al. 2022

Molecular Metabolism

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Low‐density lipoprotein receptor (LDLR) is an independent adverse prognostic factor in acute myeloid leukaemia

Cited by 18 publications

References 38 publications

Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis

Investigation of the Effect of Curcumin on Protein Targets in NAFLD Using Bioinformatic Analysis

Target Deconvolution of Fenofibrate in Nonalcoholic Fatty Liver Disease Using Bioinformatics Analysis

New dawn for cancer cell death: Emerging role of lipid metabolism

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