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Liver fibrosis can be reversed by removing its causative injuries; however, the molecular mechanisms mediating the resolution of liver fibrogenesis are poorly understood. We investigate the role of a scaffold protein, A-Kinase Anchoring Protein 12 (AKAP12), during liver fibrosis onset, and resolution. Biliary fibrogenesis and fibrosis resolution was induced in wild-type (WT) or AKAP12-deficient C57BL/6 mice through different feeding regimens with 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing chow. AKAP12 expression in portal fibroblasts (PFs) and liver sinusoidal endothelial cells (LSECs) gradually decreased as fibrosis progressed but was restored after cessation of the fibrotic challenge. Histological analysis of human liver specimens with varying degrees of fibrosis of different etiologies revealed that AKAP12 expression diminishes in hepatic fibrosis from its early stages onward. AKAP12 KO mice displayed reduced fibrosis resolution in a DDC-induced biliary fibrosis model, which was accompanied by impaired normalization of myofibroblasts and capillarized sinusoids. RNA sequencing of the liver transcriptome revealed that genes related to ECM accumulation and vascular remodeling were mostly elevated in AKAP12 KO samples. Gene ontology (GO) and bioinformatic pathway analyses identified that the differentially expressed genes were significantly enriched in GO categories and pathways, such as the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Knockdown of the AKAP12 gene in cultured primary PFs revealed that AKAP12 inhibited PF activation in association with the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Moreover, AKAP12 knockdown in LSECs led to enhanced angiogenesis, endothelin-1 expression and alterations in laminin composition. Collectively, this study demonstrates that AKAP12-mediated regulation of PFs and LSECs has a central role in resolving hepatic fibrosis.
Pubmed ID: 29700280
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Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsA commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.
View all literature mentionsSoftware tool that removes adapter sequences from DNA sequencing reads.
View all literature mentionsSoftware tool for transcriptome assembly and differential expression analysis for RNA-Seq. Includes script called cuffmerge that can be used to merge together several Cufflinks assemblies. It also handles running Cuffcompare as well as automatically filtering a number of transfrags that are likely to be artifacts. If the researcher has a reference GTF file, the researcher can provide it to the script to more effectively merge novel isoforms and maximize overall assembly quality.
View all literature mentionsSoftware to align single and paired end reads as short as 14 nt and of arbitrarily long length. Can detect short and long distance splicing, including interchromosomal splicing, in individual reads, using probabilistic models or database of known splice sites. Permits SNP-tolerant alignment to reference space of all possible combinations of major and minor alleles, and can align reads from bisulfite-treated DNA for study of methylation state.
View all literature mentionsSoftware integrated platform used for obtaining 3D structural information from single particle cryo-EM data. Enables automated, high quality and high-throughput structure discovery of proteins, viruses and molecular complexes for research and drug discovery.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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