The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice

Massey, Veronica; Dolin, Christine E.; Poole, Lauren G.; Hudson, Shanice V.; Siow, Deanna; Brock, Guy; Merchant, Michael L.; Wilkey, Daniel W.; Arteel, Gavin E.

doi:10.1002/hep.28918

Cited by 56 publications

(66 citation statements)

References 51 publications

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“…FN, a key constituent of the ECM, is a glycoprotein produced and secreted by several cell types in the liver, and its expression is associated with hepatic fibrosis, cellular damage, differentiation, and repair . In this context, FN production by activated epithelial cells is an important and potentially reversible step in the progression of biliary fibrosis . Cholangiocyte‐derived FN constitutes an important paracrine molecule in cirrhosis that is subsequently converted by HSC from a soluble protein into an insoluble matrix constituent .…”

Section: Discussionmentioning

confidence: 99%

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

et al. 2019

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During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF-β). The result is an epigenetically regulated transcriptional program leading to a pro-fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF-β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF-β. Ingenuity pathway analysis identified "HSC Activation" as the highly up-regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF-β response. EZH2 overexpression suppressed TGF-β-induced FN protein in vitro, suggesting FN as a direct target of EZH2-based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2-mediated tri-methylation of lysine 27 on histone 3 is diminished by TGF-β. TGF-β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N-recognin 4 in complex with EZH2, which was validated by western blotting in vitro. Ubiquitin mutation studies suggested K63-based ubiquitin linkage and chain elongation on EZH2 in response to TGF-β. A deletion mutant of EZH2, lacking its N-terminal domain, abrogates both TGF-β-stimulated EZH2 degradation and FN release. In vivo, cholangiocyte-selective knockout of EZH2 exacerbates bile duct ligation-induced fibrosis whereas MDR2 -/mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF-β regulates proteasomal degradation of EZH2 through N-terminal, K63-linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

et al. 2019

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“…[63][64][65] We recently demonstrated that the hepatic matrisome changes robustly to acute injury (e.g., acute lipopolysaccharide), even under conditions in which the ECM appears histologically unchanged. 45 These subhistologic transitional changes to the matrisome appear to resolve after acute injury 66,67 (►Fig. 1); with chronic injury, the transitional matrisome is replaced by collagenous scarring in the liver, which is again in-line with subcutaneous wound healing.…”

Section: Before Fibrosismentioning

confidence: 99%

The Matrisome, Inflammation, and Liver Disease

Dolin

Arteel

2020

Semin Liver Dis

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Chronic fatty liver disease is common worldwide. This disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation) to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of chronic liver disease is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) that ultimately impairs the function of the organ. The role of the ECM in early stages of chronic liver disease is less well-understood, but recent research has demonstrated that several changes in the hepatic ECM in prefibrotic liver disease are not only present but may also contribute to disease progression. The purpose of this review is to summarize the established and proposed changes to the hepatic ECM that may contribute to inflammation during earlier stages of disease development, and to discuss potential mechanisms by which these changes may mediate the progression of the disease.

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“…We further proposed to classify the matrisome into the core matrisome, which is the compendium of genes encoding proteins forming the structure of the ECM (collagens, glycoproteins, and proteoglycans), and the matrisome-associated ensemble comprising genes encoding accessory proteins and proteins involved in the remodeling of the ECM [9,10,13]. The adoption of these definitions by the scientific community has allowed the identification of ECM proteins previously unsuspected to play roles in physiological or pathological processes [14][15][16] and of ECM signatures in -omic datasets predictive, for example, of cancer patient outcomes [7,[17][18][19]. This prompted us and others to further define the matrisome of several model organisms: zebrafish [20], Caenorhabditis elegans [21], and planarians [22].…”

Section: Introductionmentioning

confidence: 99%

In-silicodefinition of theDrosophila melanogastermatrisome

Davis

Horne‐Badovinac

Naba

2019

Preprint

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The extracellular matrix (ECM) is an assembly of hundreds of proteins that structurally supports the cells it surrounds and biochemically regulates their functions. Drosophila has emerged as a powerful model organism to study fundamental mechanisms underlying ECM protein secretion, ECM assembly, and ECM roles in pathophysiological processes. However, as of today, we do not possess a well-defined list of the components forming the ECM of this organism. We previously reported the development of computational pipelines to define the matrisome -the ensemble of genes encoding ECM and ECM-associated proteins -of humans, mice, zebrafish and C. elegans.Using a similar approach, we report here that the Drosophila matrisome is composed of 641 genes.We further classify these genes into different structural and functional categories, including an expanded way to classify genes encoding proteins forming apical ECMs. We illustrate how having a comprehensive list of Drosophila matrisome proteins can be used to annotate large proteomic datasets and identify unsuspected roles for the ECM in pathophysiological processes. Last, to aid the dissemination and usage of the proposed definition and categorization of the Drosophila matrisome by the scientific community, our list has been made available through three public portals: The Matrisome Project, FlyBase, and GLAD.

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The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice

Cited by 56 publications

References 51 publications

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis

The Matrisome, Inflammation, and Liver Disease

In-silicodefinition of theDrosophila melanogastermatrisome

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