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Zhou, Chan

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Zhou

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Chan

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Zhou, Chan

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2016 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.fc6ae4e0-a583-42b8-9fd2-32c4e5f27000

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    Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells
    (Nature Publishing Group, 2017) Chen, Jennifer Yin-zu; Newcomb, Benjamin; Zhou, Chan; Pondick, Joshua V.; Ghoshal, Sarani; York, Samuel R.; Motola, Daniel L.; Coant, Nicolas; Yi, Jae Kyo; Mao, Cungui; Tanabe, Kenneth; Bronova, Irina; Berdyshev, Evgeny V.; Fuchs, Bryan; Hannun, Yusuf; Chung, Raymond; Mullen, Alan
    Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.
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    Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins
    (BioMed Central, 2016) Zhou, Chan; York, Samuel R.; Chen, Jennifer Yin-zu; Pondick, Joshua V.; Motola, Daniel L.; Chung, Raymond; Mullen, Alan
    Background: Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis. Methods: We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-β) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types. Results: We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-β, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-β signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease. Conclusions: lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0285-0) contains supplementary material, which is available to authorized users.