Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Lü, Jing; Zhang, Jie; Wang, Yan; Sun, Quan

doi:10.3390/ijms19061729

Cited by 38 publications

(30 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides, we observed CAV2 protein expression was reduced after CCl 4 treatment and recovered by subsequent antagomiR-199-3p injection, and the corresponding changes of TGFβRI expression in the opposite way, accompanied by decreased dynamin in CCl 4 -treated group and increased dynamin in antagomiR-199a-3p group, indicating the inhibited endocytosis in the CCl 4 -treated group and active endocytosis in antagomiR-199a-3p group. And CAV1 expression was reduced in the CCl 4 -treated group, consistent with previous reports, 29 but not reversed by subsequent antagomiR-199-3p injection. Taken together, these results indicate that silencing miR-199a-3p attenuates CCl 4 -induced liver fibrosis in mice, implying the potential of miR-199a-3p as a target for the treatment of hepatic fibrosis in vivo.…”

Section: Mir-199a-3p Expression Is Controlled By Twist1 In Hscssupporting

confidence: 91%

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Yang

Rong

et al. 2020

Sig Transduct Target Ther

View full text Add to dashboard Cite

The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl 4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl 4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.

show abstract

Section: Mir-199a-3p Expression Is Controlled By Twist1 In Hscssupporting

confidence: 91%

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Yang

Rong

et al. 2020

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The 2-fold gain in the cAMP production observed in the absence of Cav1 suggests that Cav1 and/or caveolae inhibit tmACs activity in melanocytes. Several studies have reported that caveolae could regulate the activity of various signaling molecules, mostly in an inhibitory fashion, through direct binding to the c aveolin-1 s caffolding d omain (CSD; Lu et al, 2018; Weng et al, 2017). Indeed, the catalytic activity of specific tmACs isoforms can be inhibited by a cell-permeable synthetic peptide which mimics the Cav1 CSD (Toya et al, 1998), and herein after referred to as CavTratin.…”

Section: Resultsmentioning

confidence: 99%

Caveolae coupling of melanocytes signaling and mechanics is required for human skin pigmentation

Domingues

Hurbain

Gilles-Marsens

et al. 2019

Preprint

View full text Add to dashboard Cite

22Tissue homeostasis requires regulation of cell-cell communication, which relies on signaling 23 molecules and cell contacts. In skin epidermis, keratinocytes secrete specific factors transduced 24 by melanocytes into signaling cues to promote their pigmentation and dendrite outgrowth, while 25 melanocytes transfer melanin pigments to keratinocytes to convey skin photoprotection. How 26 epidermal cells integrate these functions remains poorly characterized. Here, we found that 27 caveolae polarize in melanocytes and are particularly abundant at melanocyte-keratinocyte 28 interface. Caveolae in melanocytes are sensitive to ultra-violet radiations and miRNAs released 29 by keratinocytes. Preventing caveolae formation in melanocytes results in increased production 30 of intracellular cAMP and melanin pigments, but decreases cell protrusions, cell-cell contacts, 31 pigment transfer and epidermis pigmentation. Altogether, our data establish that, in 32 melanocytes, caveolae serve as key molecular hubs that couple signaling outputs from 33 keratinocytes to mechanical plasticity. This process is crucial to maintain cell-cell contacts and 34 intercellular communication, skin pigmentation and tissue homeostasis. 84Epidermal melanocytes and keratinocytes are in constant communication, not only via secreted 85 factors and exosomes that modulate cellular responses, but also by the physical contacts they 86 establish to maintain the tissue homeostasis and pigmentation. Here, we report a new function 87 for caveolae, which, by integrating the biochemical and mechanical behavior of melanocytes, 88 control melanin transfer to keratinocytes and epidermis pigmentation. Altogether, this study 89 provides the first evidence for a physiologic role of caveolae as a molecular sensing platform 90 required for the homeostasis of the largest human tissue, the skin epidermis. 91 5 Results 92 Caveolae polarize in melanocytes and are positively-regulated by keratinocytes-secreted 93 factors 94Melanocytes and keratinocytes establish a complex intercellular dialogue required for skin 95 photoprotection. 2D-co-culture systems, where these two cell types share the same medium, 96have been widely used to study intercellular communication and pigment transfer between 97 epidermal cells (Hirobe, 2005; Lei et al., 2002). To evaluate the distribution of caveolae within 98 the epidermal unit in 2D, normal human melanocytes and keratinocytes were co-cultured and 99 labelled for the two constituents of caveolae, Cav1 or Cavin1. Immunofluorescence microscopy 100 revealed that both Cav1 and Cavin1, and therefore caveolae, were asymmetrically distributed in 101 melanocytes (Figures 1A and B), which were identified by the abundant staining of the 102 premelanosome protein PMEL [hereafter referred as melanin, see Experimental Procedures; 103 (Raposo et al., 2001)]. This polarization was not observed in keratinocytes.104 Cells can break their symmetry in response to local external chemical and/or mechanical cues 105 such as signaling molecules and/or cell-ce...

show abstract

“…Cav1 deficiency was found to aggravate CCl 4 -induced liver fibrosis in mice, which was mechanistically linked to enhanced TGF-β induced oxidative stress [57]. Further, a Cav1 scaffolding domain (CSD) peptide attenuated CCl 4 -induced liver fibrosis as shown by significantly decreased collagen content [58]. The authors showed that Cav1 knockdown led to enhanced TGF-β signaling and SMAD2 phosphorylation.…”

Section: Regulation Of the Tgf-β Pathwaymentioning

confidence: 99%

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Dewidar

Meyer

Dooley

et al. 2019

Cells

555

363

View full text Add to dashboard Cite

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

show abstract

Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice

Cited by 38 publications

References 37 publications

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

Caveolae coupling of melanocytes signaling and mechanics is required for human skin pigmentation

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Contact Info

Product

Resources

About