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Altered AKAP12 expression in portal fibroblasts and liver sinusoids mediates transition from hepatic fibrogenesis to fibrosis resolution.

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Author(s)
Sung-Jin BaeJi Hae SeoJi Hyun ParkSoo Hyung RyuDanbi LeeMyoung Kuk JangEunsil YuYoung-Hwa ChungKyu-Won KimHee-Jun WeeHye Shin LeeJinhyeok ChoiTaekwon Son
Keimyung Author(s)
Seo, Ji Hye
Department
Dept. of Biochemistry (생화학)
Journal Title
Experimental & Molecular Medicine
Issued Date
2018
Volume
50
Issue
4
Abstract
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.
Keimyung Author(s)(Kor)
서지혜
Publisher
School of Medicine (의과대학)
Citation
Sung-Jin Bae et al. (2018). Altered AKAP12 expression in portal fibroblasts and liver sinusoids mediates transition from hepatic fibrogenesis to fibrosis resolution. Experimental & Molecular Medicine, 50(4), 48–48. doi: 10.1038/s12276-018-0074-5
Type
Article
ISSN
1226-3613
DOI
10.1038/s12276-018-0074-5
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41061
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
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