Activin B promotes the initiation and progression of liver fibrosis

Wang, Yan; Hamang, Matthew; Culver, Alexander; Jiang, Huaizhou; Yanum, Jennifer Abla; García, Verónica; Lee, Joonyong; Kusumanchi, Praveen; Chalasani, Naga; Liangpunsakul, Suthat; Yaden, Benjamin C.; Dai, Guoli

doi:10.1002/hep4.2037

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…We further experimentally validated that activins A and B promote HSC activation in vitro. It was recently shown that both hepatic and circulating activin B are increased in patients with MASH and alcoholic cirrhosis, and neutralizing activin B with antibodies largely prevented liver fibrosis in the CCl 4 -induced liver injury mouse model ( 39 ). Another recent study indicated that activin A can activate HSCs indirectly by inducing TNFα and TGFβ in Kupffer cells (liver macrophages) ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease

Hu,

Rychik,

Zhao

et al. 2024

Sci. Transl. Med.

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The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type–specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first “responder” in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A’s transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease

Hu,

Rychik,

Zhao

et al. 2024

Sci. Transl. Med.

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“…Hepatic fibrosis was induced by 10 mL/kg intraperitoneal injections of 1:10 diluted carbon tetrachloride (CCl 4 ) (Sigma Aldrich, St. Louis, MO, USA) in corn oil twice weekly for a total of 6 to 9 weeks for chronic studies [28]. For acute studies, tissues were harvested 6, 24, or 48 h following a single injection of CCl 4 .…”

Section: Carbon Tetrachloride Liver Fibrosis Modelmentioning

confidence: 99%

GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting

et al. 2023

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Patients with end-stage liver disease exhibit progressive skeletal muscle atrophy, highlighting a negative crosstalk between the injured liver and muscle. Our study was to determine whether TGFβ ligands function as the mediators. Acute or chronic liver injury was induced by a single or repeated administration of carbon tetrachloride. Skeletal muscle injury and repair was induced by intramuscular injection of cardiotoxin. Activin type IIB receptor (ActRIIB) ligands and growth differentiation factor 8 (Gdf8) were neutralized with ActRIIB-Fc fusion protein and a Gdf8-specific antibody, respectively. We found that acute hepatic injury induced rapid and adverse responses in muscle, which was blunted by neutralizing ActRIIB ligands. Chronic liver injury caused muscle atrophy and repair defects, which were prevented or reversed by inactivating ActRIIB ligands. Furthermore, we found that pericentral hepatocytes produce excessive Gdf8 in injured mouse liver and cirrhotic human liver. Specific inactivation of Gdf8 prevented liver injury-induced muscle atrophy, similar to neutralization of ActRIIB ligands. Inhibition of Gdf8 also reversed muscle atrophy in a treatment paradigm following chronic liver injury. Direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as that observed with liver injury. The results indicate that injured liver negatively communicate with the muscle largely via Gdf8. Unexpectedly, inactivation of Gdf8 simultaneously ameliorated liver fibrosis in mice following chronic liver injury. In vitro, Gdf8 induced human hepatic stellate (LX-2) cells to form a septa-like structure and stimulated expression of profibrotic factors. Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver–muscle negative crosstalk along with liver injury progression.

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“…Therefore, the factors that induce CAF phenotype and its molecular targets in GC still need to be fully studied. Because activin B has been proved to be pleiotropic in a variety of inflammatory diseases and fibrosis [ 10 , 19 , 20 ], our research purpose focus on the possible role of INHBB in GC development and its potential contribution to microenvironment crosstalk.…”

Section: Introductionmentioning

confidence: 99%

Paracrine activin B-NF-κB signaling shapes an inflammatory tumor microenvironment in gastric cancer via fibroblast reprogramming

Jin,

Cai,

Wang

et al. 2023

J Exp Clin Cancer Res

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Background Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. Methods The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. Results Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1β. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. Conclusions GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.

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Activin B promotes the initiation and progression of liver fibrosis

Cited by 7 publications

References 51 publications

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease

GDF8 Contributes to Liver Fibrogenesis and Concomitant Skeletal Muscle Wasting

Paracrine activin B-NF-κB signaling shapes an inflammatory tumor microenvironment in gastric cancer via fibroblast reprogramming

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