Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells

Yang, Yang; Zeng, Qingxiang; Zou, Min; Zeng, Jing; Nie, Jiao; Chen, Dongfeng; Gan, Hu

doi:10.3389/fphar.2021.663774

Cited by 10 publications

(7 citation statements)

References 35 publications

(41 reference statements)

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“…Clinical research found that plasma saturated fatty acids was associated with the incidence of sudden cardiac death in patients suffering hemodialysis, which was largely dependent on the impairment of FAO in CKD patients and animal models with tubulointerstitial fibrosis [56]. FAO has also been shown to directly promote cell-mediated ECM degradation especially through PPAR, a ligand-activated nuclear hormone receptor that binds to specific DNA response elements to regulate gene transcription and control a plethora of cellular functions associated with fibrosis-related processes, which is countered by TGFβ in nearly all fibrotic tissues, including those of the lung, liver, kidney, and bowel [24, 57, 58]. There are three main isoforms of PPAR (α, δ, and γ), with tissue-dependent expression and variables but overlapping roles in fatty-acid uptake, lipid metabolism, mitochondrial biogenesis, and adipogenesis.…”

Section: Metabolic Adaptions Of Fibroblast Activationmentioning

confidence: 99%

“…Acylcarnitine (derived from FAO by CPT1), acetyl-CoA, and fatty-acid β-oxidation breakdown products were greatly elevated. Concordantly, markedly enhanced oxygen consumption rate and expression of FAO-related genes in fibroblast cells was detected [58]. Therefore, FAO alterations in fibroblasts may differ from each other due to different organ tissues, providing diverse targets for perturbation of fatty-acid metabolism.…”

Section: Metabolic Adaptions Of Fibroblast Activationmentioning

confidence: 99%

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Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

2022

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Background: Activated fibroblasts are present in the injury response, tumorigenesis, fibrosis, and inflammation in a variety of tissues and myriad disease types. Summary: During normal tissue repair, quiescent fibroblasts transform into a proliferative and contractile phenotype termed myofibroblasts and are then lost as repair resolves to form a scar. When excessive levels are reached, activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the interstitial space of different organs. This accumulation leads to fibrotic dysfunction and multiple-organ dysfunction syndrome. To date, there are limited effective treatments for these conditions. Cellular metabolism is the cornerstone of all biological activities. Emerging evidence shows that metabolic alterations in fibroblasts are important for the activation process and illness progression. These discoveries, along with current clinical advances showing decreased lung fibrosis after targeting specific metabolic pathways, thus offer new possibilities for therapeutic interventions. The purpose of this review was to summarize the most recent knowledge of the major metabolic changes that occur during fibroblast transition from quiescent to activated states and the evidence linking alterations in fibroblast metabolism to the pathobiology of several common fibrotic diseases and tumor-related diseases. Key Messages: Metabolic disorders are associated with the progression of chronic kidney diseases. Interfering with fibroblast metabolism may be a promising therapeutic strategy for renal fibrosis and other fibrosis-related diseases.

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Section: Metabolic Adaptions Of Fibroblast Activationmentioning

confidence: 99%

Section: Metabolic Adaptions Of Fibroblast Activationmentioning

confidence: 99%

Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

2022

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“…In addition, GREM1 encoding gremlin-1 is a member of the BMP (bone morphogenic protein) antagonist family. Gremlin-1 has been demonstrated to promote the proliferation of intestinal fibroblasts [ 58 ]. Likewise, overexpression of Gremlin-1 has been shown to entail TGF-β pathway elevated ECM production and myofibroblast transition [ 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

A Comparative Analysis of the Wound Healing-Related Heterogeneity of Adipose-Derived Stem Cells Donors

et al. 2022

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Adipose-derived Stem cells (ASCs) are on the verge of being available for large clinical trials in wound healing. However, for developing advanced therapy medicinal products (ATMPs), potency assays mimicking the mode of action are required to control the product consistency of the cells. Thus, greater effort should go into the design of product assays. Therefore, we analyzed three ASC-based ATMPs from three different donors with respect to their surface markers, tri-lineage differentiation, proliferation, colony-forming unit capacity, and effect on fibroblast proliferation and migration, endothelial proliferation, migration, and angiogenesis. Furthermore, the transcriptome of all three cell products was analyzed through RNA-sequencing. Even though all products met the criteria by the International Society for Cell and Gene Therapy and the International Federation for Adipose Therapeutics and Science, we found one product to be consistently superior to others when exploring their potency in the wound healing specific assays. Our results indicate that certain regulatory genes associated with extracellular matrix and angiogenesis could be used as markers of a superior ASC donor from which to use ASCs to treat chronic wounds. Having a panel of assays capable of predicting the potency of the product would ensure the patient receives the most potent product for a specific indication, which is paramount for successful patient treatment and acceptance from the healthcare system.

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“…Gremlin-1 (GREM1) belongs to the family of BMP antagonists and is upregulated in mice and clinical patients with pulmonary fibrosis [ 14 , 15 , 16 ]. An increasing number of studies have demonstrated that GREM1 has a profibrotic effect and contributes to pulmonary fibrosis [ 15 , 16 , 17 , 18 ], renal fibrosis [ 19 ] and colonic fibrosis [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Demethyleneberberine Alleviates Pulmonary Fibrosis through Disruption of USP11 Deubiquitinating GREM1

Ge,

Huang,

Han

et al. 2024

Pharmaceuticals

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Background: Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic interstitial lung disease. Intricate pathogenesis of pulmonary fibrosis and only two approved medications with side effects and high cost bring us the challenge of fully understanding this lethal disease and urgency to find more safe and low-cost therapeutic alternatives. Purpose: Demethyleneberberine (DMB) has been demonstrated to have various anti-inflammatory, antioxidant, antifibrosis and anti-cancer bioactivities. The objective of this study was to evaluate the effect of DMB on pulmonary fibrosis and investigate the mechanism. Methods: Bleomycin (BLM)-induced pulmonary fibrosis was established in mice to evaluate the antifibrotic effect of DMB in vivo. A549 and MRC5 cells were used to evaluate the effect of DMB on epithelial–mesenchymal transition (EMT) and fibroblast–myofibroblast transition (FMT) in vitro. High throughput sequencing, biotin–avidin system and site-directed mutagenesis were applied to explore the mechanism of DMB in alleviating pulmonary fibrosis. Results: DMB alleviated BLM-induced pulmonary fibrosis in vivo by improving the survival state of mice, significantly reducing pulmonary collagen deposition and oxidative stress and improving lung tissue morphology. Meanwhile, DMB was demonstrated to inhibit epithelial–mesenchymal transition (EMT) and fibroblast–myofibroblast transition (FMT) in vitro. High throughput sequencing analysis indicated that GREM1, a highly upregulated profibrotic mediator in IPF and BLM-induced pulmonary fibrosis, was significantly downregulated by DMB. Furthermore, USP11 was revealed to be involved in the deubiquitination of GREM1 in this study and DMB promoted the ubiquitination and degradation of GREM1 by inhibiting USP11. Remarkably, DMB was demonstrated to selectively bind to the Met776 residue of USP11, leading to disruption of USP11 deubiquitinating GREM1. In addition, DMB presented an equivalent antifibrotic effect at a lower dose compared with pirfenidone and showed no obvious toxicity or side effects. Conclusions: This study revealed that USP11/GREM1 could be a potential target for IPF management and identified that DMB could promote GREM1 degradation by inhibiting USP11, thereby alleviating pulmonary fibrosis.

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Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells

Cited by 10 publications

References 35 publications

Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

A Comparative Analysis of the Wound Healing-Related Heterogeneity of Adipose-Derived Stem Cells Donors

Demethyleneberberine Alleviates Pulmonary Fibrosis through Disruption of USP11 Deubiquitinating GREM1

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