4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.
Alexandra A TsitrinaNoreen HalimaniIrina N AndreichenkoMarat SabirovMikhail NesterchukNataliya O DashenkovaRoman RomanovElena V BulgakovaArsen S MikaelyanYuri V KotelevtsevPublished in: International journal of molecular sciences (2023)
4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin resistance. It also inhibits tumor progression and metastasis. The broad spectrum of effects suggests multiple and yet unknown targets of 4MU. Aiming at 4MU target deconvolution, we have analyzed publicly available data bases, including: 1. Small molecule library Bio Assay screening (PubChemBioAssay); 2. GO pathway databases screening; 3. Protein Atlas Database. We also performed comparative liver transcriptome analysis of mice on normal diet and mice fed with 4MU for two weeks. Potential targets of 4MU public data base analysis fall into two big groups, enzymes and transcription factors (TFs), including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism. Transcriptome analysis revealed changes in the expression of genes involved in bile acid metabolism, gluconeogenesis, and immune response. It was found that 4MU feeding decreased the accumulation of the glycogen granules in the liver. Thus, 4MU has multiple targets and can regulate cell metabolism by modulating signaling via nuclear receptors.
Keyphrases
- single cell
- data analysis
- small molecule
- immune response
- body weight
- hyaluronic acid
- insulin resistance
- big data
- healthcare
- poor prognosis
- rna seq
- transcription factor
- gene expression
- high throughput
- weight loss
- electronic health record
- type diabetes
- genome wide
- stem cells
- physical activity
- emergency department
- cell therapy
- metabolic syndrome
- machine learning
- climate change
- protein protein
- inflammatory response
- adverse drug
- toll like receptor
- drug induced
- liver fibrosis
- replacement therapy