Lin 28A/Occludin axis: An aberrantly activated pathway in intestinal epithelial cells leading to impaired barrier function under total parenteral nutrition.

Yang Liu, Zizhen Gong, Jiefei Zhou, Junkai Yan, Wei Cai

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2021 Feb

filter terms:

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. © 2020 Federation of American Societies for Experimental Biology.

Citation

Yang Liu, Zizhen Gong, Jiefei Zhou, Junkai Yan, Wei Cai. Lin 28A/Occludin axis: An aberrantly activated pathway in intestinal epithelial cells leading to impaired barrier function under total parenteral nutrition. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021 Feb;35(2):e21189