Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice

Osawa, Yosuke; Oboki, Keisuke; Imamura, Jun; Kojika, Ekumi; Hayashi, Yukiko; Hishima, Tsunekazu; Saibara, Toshiji; Shibasaki, Futoshi; Kohara, Michinori; Kimura, Kiminori

doi:10.1016/j.ebiom.2015.10.010

Cited by 71 publications

(86 citation statements)

References 48 publications

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“…We had previously reported that PRI‐724, a selective inhibitor of the CBP/β‐catenin interaction, attenuates CCl 4 or BDL‐induced liver fibrosis . Similarly, PRI‐724 treatment reduced the liver fibrosis induced by an HFD plus GalN despite steatosis induction (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1158/full).…”

Section: Resultsmentioning

confidence: 99%

“…Liver macrophages contribute to liver fibrosis; depletion of liver macrophages suppresses liver fibrosis following BDL and decreases myofibroblasts in a liver tumor . Moreover, inhibition of CBP/β‐catenin promotes liver fibrosis resolution by macrophages . Although macrophages contribute to NASH development, the role of CBP/β‐catenin in liver macrophages during liver fibrosis in NASH is unclear.…”

Section: Introductionmentioning

confidence: 99%

“…(29) Moreover, inhibition of CBP/b-catenin promotes liver fibrosis resolution by macrophages. (26) Although macrophages contribute to NASH development, (30) the role of CBP/b-catenin in liver macrophages during liver fibrosis in NASH is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

Osawa

Kojika

Hayashi

et al. 2018

Hepatology Communications

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Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)‐α‐mediated hepatocyte apoptosis in the simple fatty liver triggers liver fibrosis. To address this question, high‐fat diet‐fed mice were repeatedly administered D‐galactosamine, which increases the sensitivity of hepatocytes to TNF‐α‐mediated apoptosis. In mice treated with a high‐fat diet plus D‐galactosamine, hepatocyte apoptosis and liver fibrosis were induced, whereas both apoptosis and fibrosis were inhibited in these mice following gut sterilization with antimicrobials or knockout of TNF‐α. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor κB kinase subunit β. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF‐α up‐regulation in the steatotic liver caused fibrosis. Organ fibrosis, including liver fibrosis, involves the interaction of cyclic adenosine monophosphate‐response element‐binding protein‐binding protein (CBP) and β‐catenin. Here, hepatocyte‐specific CBP‐knockout mice showed reduced liver fibrosis accompanied by hepatocyte apoptosis diminution; notably, liver fibrosis was also decreased in mice in which CBP was specifically knocked out in collagen‐producing cells because the activation of these cells was now suppressed. Conclusion: TNF‐α‐mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/β‐catenin signaling attenuated the liver fibrosis due to the reduction of hepatocyte apoptosis and suppression of the activation of collagen‐producing cells. Thus, targeting CBP/β‐catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. (Hepatology Communications 2018;2:407‐420)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

Osawa

Kojika

Hayashi

et al. 2018

Hepatology Communications

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“…Conversely, HSC-derived delta-like homolog 1 (DLK1) activates HSCs via epigenetic PPARγ repression and promote liver regeneration [152]. A selective inhibitor of the cAMP-response element-binding protein (CBP)/β-catenin interaction, PRI-724, inhibits HSC activation and reduces liver fibrosis in mice [153]. In contrast, β-catenin-dependent canonical Wnt activation is required to maintain quiescent state of HSCs in vitro [154].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,087

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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“…Similar to ICG-001, PRI-724 inhibits recruitment of beta-catenin to its coactivator, CBP (NCI, 2014). PRI-724 blocks carbon tetrachloride and bile duct ligation induced liver fibrosis in mice (Osawa et al, 2015). C-82 has not been previously administered in any form including topical in humans.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82

Lafyatis

Mantero

Gordon

et al. 2017

Journal of Investigative Dermatology

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Several studies have suggested that Wnts might contribute to skin fibrosis in systemic sclerosis (SSc) by affecting the differentiation of pluripotent dermal cells. We tested C-82, a therapeutic that inhibits canonical Wnt signaling by blocking the interaction of cAMP Response Element-Binding Protein with β-Catenin and inhibiting Wnt-activated genes. We utilized previously unreported trial design, formulating C-82 for topical application and conducting a placebo controlled, double-blinded clinical trial in which patients with diffuse cutaneous SSc were treated with C-82 or placebo on opposite forearms. C-82 compared to placebo treated forearms did not show any clinical effect. Skin biopsies performed before and after treatment showed a very weak trend toward improvement in the C-82 treated skin of biomarkers of local skin disease, THBS1 and COMP. However, on microarray analysis C-82 treatment strongly upregulated two clusters of genes that correlate negatively with the severity of SSc skin disease. These clusters are highly associated with metabolism and one gene, PLIN2, expressed only by sebocytes and subcutaneous fat cells. These changes in gene expression strongly support a role for Wnts in differentiation of pluripotent cells into profibrotic fibroblasts, and the potential for C-82 with longer treatment to promote fat regeneration in SSc skin.

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Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice

Cited by 71 publications

References 48 publications

Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

Tumor necrosis factor‐α‐mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice

Hepatic stellate cells as key target in liver fibrosis

Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82

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