Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

Chung, Sook In; Moon, Hyuk; Ju, Hye Lim; Cho, Kyung Joo; Kim, Do Young; Han, Kwang Hyub; Eun, Jung Woo; Nam, Suk Woo; Ribback, Silvia; Dombrowski, Frank; Calvisi, Diego F.; Ro, Simon Weonsang

doi:10.1016/j.jhep.2015.10.007

Cited by 100 publications

(73 citation statements)

References 49 publications

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“…In adult kidneys, however, Shh expression is largely silenced. Re-activation of Shh signaling has been implicated in the pathogenesis of tissue fibrosis in many organs including kidney, lung and liver (Chung et al, 2016; Cigna et al, 2012; Zhou et al, 2014). …”

Section: Shh Signaling and Ckdmentioning

confidence: 99%

“…Unlike lung, Shh is found in both ballooned hepatocyte and hepatic stellate cells in the liver of NAFLD, which eventually leads to liver fibrosis or cirrhosis (Hirsova and Gores, 2015; Rangwala et al, 2011). By using hydrodynamics-based gene transfer approach, hepatic expression of Shh induces liver fibrosis, which is accompanied by concurrent activation of hepatic stellate cells, and upregulation of various fibrogenic genes (Chung et al, 2016). Meanwhile, hepatic stellate cells could produce Shh through an autocrine fashion to accelerate progression of liver diseases.…”

Section: Shh Signaling and The Fibrotic Disease Of Other Organsmentioning

confidence: 99%

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Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

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Section: Shh Signaling and Ckdmentioning

confidence: 99%

Section: Shh Signaling and The Fibrotic Disease Of Other Organsmentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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“…Chronic hepatocyte damage caused by CCl 4 treatment eventually induces fibrosis [11]. Mice after the treatment with CC1 4 for 6 weeks displayed marked increases in inflammatory cell infiltration, hepatic steatosis, collagen deposition, and disruption of the lobular liver architecture (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hepatic fibrosis is characterized by progressive inflammation and excessive deposition of extracellular matrix (ECM) [1, 11]. Hepatic stellate cells (HSCs) the main collagen-producing cells in the damaged liver.…”

Section: Discussionmentioning

confidence: 99%

“…Liver transplant has also been reported to improve the composition of the gut microbiome and cognitive impairment in cirrhotic patients [12]. Increased translocation of bacteria and bacterial products from the intestine may impair liver homeostasis and enhance liver inflammation through activation of the innate immune system [11, 29]. Specifically, activation of TLR4 stimulates macrophages and HSC activation.…”

Section: Discussionmentioning

confidence: 99%

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Xia-Yu-Xue Decoction Inhibits Intestinal Epithelial Cell Apoptosis in CCl4-Induced Liver Fibrosis

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Intestine-derived endotoxin is thought to play a role in the development of liver fibrosis. However, the pathological change in the intestine during liver fibrosis is still poorly understood. Here, we investigated the effects of Xia-yu-xue decoction (XYXD) on intestinal inflammation, apoptosis, and tight junction integrity in the carbon tetrachloride (CCl₄)-induced liver fibrosis. Methods: Murine liver fibrosis was developed by CCI₄ treatment three times per week over a 6-week period. The CCl₄-treated mice were divided into two groups: the CCl₄-water group (n=8, CCl₄) and the CCl₄-XYXD group (n=8, CCl₄+XYXD). The CCl₄+XYXD mice were treated with XYXD from the beginning of the first week. The expression of inflammatory cytokines and apoptotic molecules were examined using immunohistochemistry, real-time PCR, and western blot. The intestinal epithelial cell apoptosis was examined by TUNEL staining. The tight junction-related molecules, such as ZO-1, claudin, and occludin in the gut were measured by real-time PCR. Results: In CCl₄-treated mice damage of the intestinal epithelia and infiltration of inflammatory cells into the lamina propria and muscular layer were observed. Proinflammatory markers MCP-1, TNF-α, CXCL11, IL-6, and CD68 were significantly increased in the intestinal epithelia in CCI₄-treated mice. The expression of pro-apoptotic molecules including Fas and Bax was increased in the intestinal epithelia in CCI₄-treated mice compared with that in control. The number of TUNEL-positive intestinal epithelial cells was also markedly increased in CCl₄-treated mice. The expression of the tight junction proteins including ZO-1, claudin, and occludin was significantly decreased in CCI₄-treated mice compared with that in control mice. Notably, XYXD treatment ameliorated increased inflammatory markers and apoptosis-related molecules and decreased tight-junction proteins in CCl₄-treated mice. Conclusion: CCl₄-treatment increased expression of proinflammatory cytokines and pro-apoptotic molecules and disrupted tight junction integrity in the intestine. XYXD treatment ameliorated intestinal inflammation, cell death, and tight junction disintegrity induced by CCl₄ treatment, suggesting that XYXD inhibits CCl₄-mediated liver fibrosis at least in part by ameliorating the intestinal epithelial damage.

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Developmental Morphogens and Adult Liver Repair

Machado

Diehl

2020

The Liver

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Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

Cited by 100 publications

References 49 publications

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Xia-Yu-Xue Decoction Inhibits Intestinal Epithelial Cell Apoptosis in CCl4-Induced Liver Fibrosis

Developmental Morphogens and Adult Liver Repair

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