Inhibition of LncRNA-NEAT1 alleviates intestinal epithelial cells (IECs) dysfunction in ulcerative colitis by maintaining the homeostasis of the glucose metabolism through the miR-410-3p-LDHA axis

Abstract

Dysfunction of intestinal epithelial cells (IECs) leads to intestinal epithelial barrier damage and critically involves in the pathogenesis and development of ulcerative colitis (UC). Accumulating studies revealed essential functions of non-coding RNAs in UC. LncRNA NEAT1 (long non-coding RNA nuclear paraspeckle assembly transcript 1) is frequently dysregulated in diverse human diseases. Currently, the precise roles of NEAT1 in the dysfunction of IECs during UC remain unclear. We report NEAT1 was significantly upregulated in IECs from UC patients. In addition, microRNA-410-3p was remarkedly suppressed in IECs from UC patients. Silencing NEAT1 effectively ameliorates the LPS-induced IECs dysfunction. Bioinformatical analysis, RNA pull-down and luciferase assays illustrated that NEAT1 sponged miR-410-3p to downregulate its expression in IECs. Interestingly, the glucose metabolism was obviously elevated in IECs from UC compared with normal colon tissues. Furthermore, NEAT1 promoted and miR-410-3p suppressed glucose metabolism of IECs. We identified lactate dehydrogenase A (LDHA), a glucose metabolism key enzyme, was a direct target of miR-410-3p in IECs. Rescue experiments verified that restoration of miR-410-3p in NEAT1-overexpressing IECs successfully overcame the NEAT1-promoted cell death under LPS treatment by targeting LDHA. In summary, these results unveiled new roles and molecular mechanisms for the NEAT1-mediated IECs dysfunction during the ulcerative colitis.

Identification of Critical Modules and Biomarkers of Ulcerative Colitis by Using WGCNA

“…In addition, the lncRNAs XIST and NEAT1 have been linked to the process of inflammation in UC. [77][78][79] The predicted lncRNA XIST, together with two essential miRNAs, may all play important roles in UC progression. Nonetheless, the ceRNA mechanisms underlying UC remained mostly unclear, demanding more study.…”

LDHA: The Obstacle to T cell responses against tumor

“…In gastric cancer, lncRNA-HAGLR sponged miR-338-3p while LDHA was the direct target of miR-338-3p ( 66 ). Additionally, a recent study demonstrated that lncRNA-NEAT1 sponged miR-410-3p to downregulate its expression, thereby inhibiting LDHA in intestinal epithelial cells (IECs) ( 67 ).…”

Comprehensive analysis of disulfidptosis-related genes reveals the effect of disulfidptosis in ulcerative colitis

“…Disulfide stress induced by disulfide accumulation is the key factor leading to disulfidptosis. Studies have shown that glucose metabolism in the intestinal epithelial cells of UC is dramatically enhanced and glucose consumption is significantly increased due to the persistence of chronic inflammation 10 . Moreover, due to the restricted dietary structure, intestinal mucosal damage leads to nutrient absorption disorder and long-term diarrhea, and the intake and absorption of glucose in patients with UC are decreased significantly.…”

“…The above factors suggest that a relative lack of glucose or even glucose starvation may exist in the intestinal mucosal tissues of UC patients, which is the critical basis for disulfidptosis in the UC intestinal mucosa. It has been reported in the literature that the expression of SLC3A2, which is a chaperone protein that together with SLC7A11 constitutes the glutamate-cystine countertransport system (system XC-) and participates in the intracellular transport of cystine, is upregulated in UC 10 – 14 , and the content of cystine in the intestinal mucosa of UC is significantly elevated compared with that of normal mucosa 15 . This result suggests that there may be an excessive accumulation of cystine in the UC intestinal mucosa, resulting in a relative deficiency of intracellular NADPH, which is unable to completely reduce the excessive cystine, leading to the accumulation of disulfides and the occurrence of disulfide stress, which is also a key condition for the occurrence of disulfidptosis in the UC intestinal mucosa.…”