Wnt signaling in liver fibrosis: Progress, challenges and potential directions

Miao, Chenggui; Yang, Yingying; He, Xu; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Jin, Yong; Li, Jun

doi:10.1016/j.biochi.2013.09.003

Cited by 118 publications

(94 citation statements)

References 89 publications

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“…Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 restores gene expression of PPARγ and inhibits the activation of HSC. 51 We observed in this report that the expression of exogenous Plin5 induced the activity of LXR and PPARγ, and interrupted the canonical Wnt signal pathway, as well as stimulated the expression of SREBP-1c in HSC. These effects collectively promoted the expression of pro-lipogenic genes and facilitated the elevation of cellular lipid content in HSC.…”

Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 62%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

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Section: Plin5 Restores Ld Formation In Hscmentioning

confidence: 62%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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“…Suppressing the expression of these proteins enhances organ fibrosis. This is not only true for the kidney, but similar mechanisms exist also in the liver and skin [9,10].…”

mentioning

confidence: 84%

Regulation of endogenous brakes to kidney fibrosis: turning the view upside down

2017

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“…Normally, the Wnt signaling pathway can be categorized as either the canonical Wnt pathway or non-canonical Wnt pathway (88). In the canonical Wnt pathway, β-catenin is the central molecule that controls the on/off 'switch' of the Wnt signaling pathway.…”

Section: Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

“…β-catenin is then captured by a protein complex, which is composed of adenomatous polyposis coli (APC), the scaffolding protein Axin, glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1) (88,89). β-catenin is phosphorylated by CK1 and GSK3β and targeted for proteasomal degradation (89), leading to decreased β-catenin concentration, inhibition of nuclear translocation of β-catenin and thus, inhibition of target gene activation (88)(89)(90). When the switch is on, a different mechanism unfolds.…”

Section: Wnt/β-catenin Signaling Pathwaymentioning

confidence: 99%

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Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

Xiao

Xin

Tang

et al. 2015

International Journal of Oncology

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Abstract. There is no radical cure for all cancer types. The most frequently used therapies are surgical treatment, radiotherapy and chemotherapy. However, recrudescence, radiation resistance and chemotherapy resistance are the most challenging issues in clinical practice. To address these issues, they should be further studied at the molecular level, and the signaling pathways involved represent a promising avenue for this research. In the present review, we mainly discuss the components and mechanisms of activation of the Notch and Wnt signaling pathways, and we summarize the recent research efforts on these two pathways in different cancers.

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Wnt signaling in liver fibrosis: Progress, challenges and potential directions

Cited by 118 publications

References 89 publications

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Regulation of endogenous brakes to kidney fibrosis: turning the view upside down

Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

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