MicroRNA-194: a novel regulator of glucagon-like peptide-1 synthesis in intestinal L cells

Abstract

In the status of obesity, the glucagon-like peptide-1 (GLP-1) level usually declines and results in metabolic syndrome. This study aimed to investigate the intracellular mechanism of GLP-1 synthesis in L cells from the perspective of microRNA (miRNA). In the present study, we found that GLP-1 level was down-regulated in the plasma and ileum tissues of obese mice, while the ileac miR-194 expression was up-regulated. In vitro experiments indicated that miR-194 overexpression down-regulated GLP-1 level, mRNA levels of proglucagon gene (gcg) and prohormone convertase 1/3 gene (pcsk1), and the nuclear protein level of beta-catenin (β-catenin). Further investigation confirmed that β-catenin could promote gcg transcription through binding to transcription factor 7-like 2 (TCF7L2). miR-194 suppressed gcg mRNA level via negatively regulating TCF7L2 expression. What’s more, forkhead box a1 (Foxa1) could bind to the promoter of pcsk1 and enhanced its transcription. miR-194 suppressed pcsk1 transcription through targeting Foxa1. Besides, the interference of miR-194 reduced palmitate (PA)-induced cell apoptosis and the anti-apoptosis effect of miR-194 inhibitor was abolished by TCF7L2 knockdown. Finally, in HFD-induced obese mice, the silence of miR-194 significantly elevated GLP-1 level and improved the metabolic symptoms caused by GLP-1 deficiency. To sum up, our study found that miR-194 suppressed GLP-1 synthesis in L cells via inhibiting TCF7L2-mediated gcg transcription and Foxa1-mediated pcsk1 transcription. Meanwhile, miR-194 took part in the PA-induced apoptosis of L cells.

Investigation of umbilical cord serum miRNAs associated with childhood obesity: A pilot study from a birth cohort study

“…Moreover, miR‐1260b directly targets the 3’UTR of growth differentiation factor 11 20 . miR‐194 was also reported to suppress the synthesis of glucagon‐like peptide‐1 in L cells 21 . Taken together, our data suggest that umbilical cord serum miRNAs may be associated with the biological process of childhood obesity and could be new biomarkers for the early identification of future obesity.…”

The role of FOXA family transcription factors in glucolipid metabolism and NAFLD

“…miR-194 inhibits GLP-1 synthesis in L cells by suppressing FOXA1-mediated transcription of pcsk1. In contrast, miR-194 silencing in HFD-induced obese mice significantly increased the levels of FOXA1, Pcsk1 and GLP-1, and both oral glucose tolerance and insulin tolerance were also attenuated ( 56 ).…”

The Regulatory Role of MicroRNAs in Obesity and Obesity-Derived Ailments

“…Additionally, it has been elucidated that in obesity, the titer of glucagon-like peptide-1 (GLP-1) declines, and this can lead to metabolic syndrome [50]. miR-194 has been identified as a regulator of GLP-1 since, in the plasma and ileum tissue of obese mice, GLP-1 was underexpressed while miR-194 was upregulated.…”

“…miR-194 has been identified as a regulator of GLP-1 since, in the plasma and ileum tissue of obese mice, GLP-1 was underexpressed while miR-194 was upregulated. In obese mice, the overexpression of miR-194 and the inhibition of GLP-1 expression led to mitochondrial dysfunction and aggravated cardiac injury [50]. Hence, miR-194 is an important biomarker in the expression of GLP-1 and in the interaction of obesity and its inherent biological mechanisms.…”