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Lin 28A/Occludin axis: An aberrantly activated pathway in intestinal epithelial cells leading to impaired barrier
Yang Liu1, Zizhen Gong1,2, Jiefei Zhou1,2
1Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Insights
Aberrantly increased Lin 28A protein in intestinal cells disrupts barrier function during total parenteral nutrition (TPN) by repressing Occludin translation, revealing a novel mechanism for TPN-induced intestinal dysfunction.
Area of Science:
- Molecular Biology
- Gastroenterology
- Cell Biology
Background:
- Intestinal barrier dysfunction, characterized by tight junction disassembly, is a significant complication of total parenteral nutrition (TPN).
- The precise molecular mechanisms underlying TPN-induced intestinal barrier defects remain incompletely understood.
- Aberrant expression of RNA binding protein Lin 28A in intestinal epithelial cells during TPN suggests a potential role in this dysfunction.
Purpose of the Study:
- To elucidate the role of Lin 28A in regulating intestinal barrier function under TPN.
- To investigate the mechanism by which Lin 28A affects tight junction proteins, specifically Occludin.
- To identify Lin 28A as a potential therapeutic target for TPN-associated intestinal complications.
Main Methods:
- Utilized a rat model of TPN to observe time-dependent changes in Lin 28A and Occludin expression.
- Employed mouse intestinal organoids and human Caco-2 cells for in vitro validation of Lin 28A's effects on Occludin.
- Performed polysomal profiling to assess translational regulation and RNA immunoprecipitation (RIP) to confirm direct binding of Lin 28A to Occludin mRNA.
Main Results:
- Lin 28A expression was upregulated in the intestines of TPN rats, inversely correlating with Occludin levels.
- Ectopic overexpression of Lin 28A in vitro significantly suppressed Occludin expression.
- Lin 28A was confirmed to bind directly to the 3' UTR of Occludin mRNA, leading to translational repression via DCP1a.
Conclusions:
- Lin 28A plays a critical role in TPN-induced intestinal barrier dysfunction by inhibiting Occludin translation.
- The Lin 28A/Occludin axis represents a novel molecular mechanism contributing to intestinal barrier defects under TPN.
- Targeting the Lin 28A pathway may offer a therapeutic strategy to mitigate TPN-related intestinal complications.
Abstract:
Disassembly of tight junctions is a major cause of intestinal barrier dysfunction under total parenteral nutrition (TPN), but the precise mechanisms have not been fully understood. Normally, RNA binding protein Lin 28A is highly restricted to embryonic stem cells and dramatically decreases as differentiation progresses; however, in our preliminary study it was found aberrantly increased in the intestinal epithelial cells of TPN rats, and thus its mechanism of action needs to be addressed. Herein, we report a pivotal role of Lin 28A in the regulation of tight junctions, which induces a sustained translational repression of Occludin, leading to disruption of intestinal barrier function under TPN. Using a rat model of TPN, we found time-dependent upregulation of Lin 28A, negatively correlated with Occludin. Using mouse intestinal organoids and human gut-derived Caco-2 cells as in vitro models, we found that expression of Occludin could be significantly suppressed by ectopic overexpression of Lin 28A. The underlying mechanisms may be partially attributed to translational repression, as the abundance of Occludin transcripts in polysomes was dramatically reduced by Lin 28A (polysomal profiling). Furthermore, Lin 28A was found to directly bind to Occludin mRNA 3' untranslated coding region (UTR), thereby repressing the translation of Occludin transcripts through decapping enzyme 1A (DCP1a). Taken together, our findings revealed that Lin 28A/Occludin axis may be a novel mechanism accounting for the development of barrier dysfunction under TPN.
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