Transcriptional Profiling of liver fibrosis induced by CCl4 injections
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PROVIDER: PRJNA922557 | ENA |
REPOSITORIES: ENA
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Project description:The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis-induced by repeated CCl4 injections in mice (n = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development - Initiation, Progression, and Tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. A public data analysis and shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the Tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.
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Project description:Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)-induced liver fibrosis using the Hybrid Mouse Diversity Panel (HMDP), a panel of over 100 genetically distinct mouse strains optimized for genome wide association studies and systems genetics. Chronic liver injury was induced by CCl4 injections twice weekly for six weeks. 437 mice received CCl4 and 256 received vehicle, after which animals were sacrificed for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area % (CPA%) of the whole section, excluding normal collagen. We discovered broad variation in fibrosis among the HMDP strains, demonstrating a significant genetic influence on this trait, with an estimated heritability (H2) of 44%. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing, and gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent. We also performed expression quantitative trait locus analyses to identify strong causal candidate genes. Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing anti-fibrotic drugs.
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Project description:This study aimed to investigate the protective mechanisms of helenalin on hepatic fibrosis,Rats were intragastrically administrated with 50% CCl4 for 9 weeks to induce liver fibrosis, followed by various medicines for 6 weeks. The transcriptomic analysis was performed in liver tissues by RNA-seq.
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Project description:This study is aimed to investigate the underlying mechanisms of didymin on anti-hepatic fibrosis. In brief, mice were randomly devided into three groups,including normal, CCl4 and didymin groups. Except the normal group, mice were intra-peritonelly administrated with 20% CCl4 for 10 weeks to induce liver fibrosis; after modeling successfully, mice in didymin group were subsequently intragastrically administrated with didymin for 6 weeks. Finally, the transcriptomic analysis was performed to acquire the differently expressed genes amog the three groups, trying to figure out the potential targets, which regulated by didymin.
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