Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans

Autor: Miha Mraz, Winnie Eskild, Žiga Urlep, Tadeja Režen, Damjana Rozman, Peter Juvan, Xiang Yi Kong, Kaja Blagotinšek Cokan, Miha Moškon
Rok vydání: 2020
Předmět:
0301 basic medicine
Liver Cirrhosis
Male
lcsh:Chemistry
Mice
0302 clinical medicine
žolčna kislina
Fibrosis
Non-alcoholic Fatty Liver Disease
lcsh:QH301-705.5
Spectroscopy
Oligonucleotide Array Sequence Analysis
Genome
GEM
Fatty liver
Fatty Acids
NASH
General Medicine
Lipids
maščobna kislina
Computer Science Applications
Liver
030211 gastroenterology & hepatology
Female
Signal Transduction
Biology
Catalysis
Article
Inorganic Chemistry
Bile Acids and Salts
03 medical and health sciences
NAFLD
Genetic model
medicine
Animals
Humans
bile acid
Physical and Theoretical Chemistry
KEGG
udc:616.3
Molecular Biology
Transcription factor
Inflammation
Organic Chemistry
fibrosis
medicine.disease
Lipid Metabolism
fibroza
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Immune System
Cancer research
fatty acid
TRANSFAC
Estrogen receptor alpha
Steroid hormone metabolism
Biomarkers
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 832, p 832 (2021)
Volume 22
Issue 2
International journal of molecular sciences, vol. 22, no. 2, 832, 2021.
ISSN: 1422-0067
Popis: Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis&mdash
Cyp51, notch signaling&mdash
Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa
B) signaling&mdash
Ikbkg, and unknown lysosomal pathway&mdash
Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ER&alpha
) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies.
Databáze: OpenAIRE
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