CELF1/p53 axis: a sustained antiproliferative signal leading to villus atrophy under total parenteral nutrition

Yan, Junkai; Zhang, Tian; Dai, Lina; Gu, Bei-Lin; Zhu, Jie; Yan, Wei; Cai, Wei; Wang, Ying

doi:10.1096/fj.201801695r

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…However, FAO seems to be deactivated in those SBS patients with intestinal failure compared to their counterparts with intestinal adaption. Given a growing body of evidence linking PN‐induced villus atrophy to intestinal failure, 34–36 we then asked by what kind of mechanism intestinal FAO was functionally inhibited in these SBS patients and PN piglets.…”

Section: Discussionmentioning

confidence: 99%

Impaired FXR‐CPT1a signaling contributes to parenteral nutrition‐induced villus atrophy in short‐bowel syndrome

et al. 2022

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Parenteral nutrition (PN)‐induced villus atrophy is a major cause of intestinal failure (IF) for children suffering from short bowel syndrome (SBS), but the precise mechanism remains unclear. Herein, we report a pivotal role of farnesoid X receptor (FXR) signaling and fatty acid oxidation (FAO) in PN‐induced villus atrophy. A total of 14 pediatric SBS patients receiving PN were enrolled in this study. Those patients with IF showed longer PN duration and significant intestinal villus atrophy, characterized by remarkably increased enterocyte apoptosis concomitant with impaired FXR signaling and decreased FAO genes including carnitine palmitoyltransferase 1a (CPT1a). Likewise, similar changes were found in an in vivo model of neonatal Bama piglets receiving 14‐day PN, including villus atrophy and particularly disturbed FAO process responding to impaired FXR signaling. Finally, in order to consolidate the role of the FXR‐CPT1a axis in modulating enterocyte apoptosis, patient‐derived organoids (PDOs) were used as a mini‐gut model in vitro. Consequently, pharmacological inhibition of FXR by tauro‐β‐muricholic acid (T‐βMCA) evidently suppressed CPT1a expression leading to reduced mitochondrial FAO function and inducible apoptosis. In conclusion, impaired FXR/CPT1a axis and disturbed FAO may play a pivotal role in PN‐induced villus atrophy, contributing to intestinal failure in SBS patients.

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Section: Discussionmentioning

confidence: 99%

Impaired FXR‐CPT1a signaling contributes to parenteral nutrition‐induced villus atrophy in short‐bowel syndrome

et al. 2022

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“…After 1‐week acclimatization, rats were randomized to sham or TPN group (n = 5‐6/group). Surgery procedure and composition of TPN solution was identical to that previously described . The TPN group received TPN delivery (400 kcal/kg/d) continuously for 7 days but was allowed water ad libitum ; the sham group received exactly same process and infused with saline and fed with standard chow ad libitum .…”

Section: Methodsmentioning

confidence: 99%

Early downregulation of P‐glycoprotein facilitates bacterial attachment to intestinal epithelial cells and thereby triggers barrier dysfunction in a rodent model of total parenteral nutrition

et al. 2020

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Intestinal barrier dysfunction is a major complication of total parenteral nutrition (TPN). Our preliminary study revealed that intestinal P‐glycoprotein (P‐gp) was significantly downregulated under TPN treatment followed by disruption of barrier function, and thus the significance of early downregulation of P‐gp needs to be addressed. Herein, we report a pivotal role of P‐gp in the development of intestinal barrier dysfunction under TPN. Functional suppression of P‐gp may facilitate bacterial attachment to intestinal epithelial cells (IECs) and thereby induce degradation of tight junctions to trigger barrier dysfunction. By using a rat model of TPN, we found early downregulation of P‐gp function in ileum after 3‐day TPN, followed by disruption of barrier function after 7‐day TPN. By using Escherichia coli (E. coli) k88 and DH5α as type strains, we found significantly increased bacterial attachment to IECs in TPN group compared to sham. By using Caco‐2 cells as an IEC model in vitro, we found that functional suppression of P‐gp remarkably facilitated bacterial attachment to Caco‐2 cells, leading to subsequent disruption of intestinal barrier function. Of note, Occludin was significantly downregulated by bacterial attachment when P‐gp was functionally suppressed. Mechanistically, changes on Occludin were attributed to enhanced protein degradation instead of suppressed protein translation. Despite the half‐life of Occludin protein being unchanged by DH5α treatment alone, it was decreased by about 40% when P‐gp was simultaneously suppressed. Taken together, our findings revealed that early downregulation of intestinal P‐gp under TPN may be a potential therapeutic target to prevent the development of barrier dysfunction.

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“…[ 83 ] Finally, activation of the CELF1 (Elav‐like family member‐1, an RNA binding protein acting as a regulator of alternative splicing, translation, and mRNA degradation)/p53 axis has been shown to mediate sustained anti‐proliferative pro‐apoptotic signaling with G2 cell arrest causing villus atrophy in a TPN rat model. [ 84 ] Interestingly, CELF1 is equally activated in fish‐, soybean‐ and olive oil‐treated Caco‐2 cells, but only olive oil‐induced apoptosis can be fully reversed by CELF1 silencing, [ 85 ] implying the involvement of different pro‐apoptotic mechanisms in response to specific fatty acids potentially released from TPN.…”

Section: Complex Problems Associated With Current Tpn Formulationsmentioning

confidence: 99%

Novel Strategies to Prevent Total Parenteral Nutrition‐Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes

Lucchinetti

Lou

Wawrzyniak

et al. 2020

Molecular Nutrition Food Res

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Total parenteral nutrition (TPN) is a life‐saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN‐associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein‐coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut‐originating incretins as well as the potentially toxicity of phytosterols and pro‐inflammatory fatty acids mainly released from soybean oil‐based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti‐inflammatory n‐3 to pro‐inflammatory n‐6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN‐associated adverse effects.

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CELF1/p53 axis: a sustained antiproliferative signal leading to villus atrophy under total parenteral nutrition

Cited by 6 publications

References 55 publications

Impaired FXR‐CPT1a signaling contributes to parenteral nutrition‐induced villus atrophy in short‐bowel syndrome

Impaired FXR‐CPT1a signaling contributes to parenteral nutrition‐induced villus atrophy in short‐bowel syndrome

Early downregulation of P‐glycoprotein facilitates bacterial attachment to intestinal epithelial cells and thereby triggers barrier dysfunction in a rodent model of total parenteral nutrition

Novel Strategies to Prevent Total Parenteral Nutrition‐Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes

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