Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA

Abstract

Our previous studies have demonstrated that stable microRNAs (miRNAs) in mammalian serum and plasma are actively secreted from tissues and cells and can serve as a novel class of biomarkers for diseases, and act as signaling molecules in intercellular communication. Here, we report the surprising finding that exogenous plant miRNAs are present in the sera and tissues of various animals and that these exogenous plant miRNAs are primarily acquired orally, through food intake. MIR168a is abundant in rice and is one of the most highly enriched exogenous plant miRNAs in the sera of Chinese subjects. Functional studies in vitro and in vivo demonstrated that MIR168a could bind to the human/mouse low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA, inhibit LDLRAP1 expression in liver, and consequently decrease LDL removal from mouse plasma. These findings demonstrate that exogenous plant miRNAs in food can regulate the expression of target genes in mammals.

Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis

“…82 Functional in vitro and in vivo studies on mice demonstrated that the binding of miR-168a to LDLRAP1 mRNA causes inhibition of its expression, and this leads to decreasing low density lipoprotein (LDL) removal from plasma and consequently increased LDL serum concentration. 78 Despite findings showing that down-regulation of LDLRAP1 raises LDL concentration, 83 the current clinical experience has not provided any evidence that rice-based diet would result in increased serum LDL concentration and potentially higher cardiovascular morbidity. 84,85 Following an initial upheaval implying that diet should be now regarded not only as a source of nutrients but also as a potential source for epigenetic, gene expression modulating miRNAs, 86 several data appear to weaken this "dietary xenomiRNA" hypothesis.…”

“…78 It was earlier known that exogenous miRNA could be detected in the blood of healthy individuals, 79,80 but this was the first report to show that a xeno-miRNA could affect gene expression in the recipient. As plant miRNAs have a different chemical structure compared to animal miRNAs (the terminal nucleotide is modified by 2 0 -O methylation in plant miRNAs), 81 plant miRNAs can be clearly identified.…”

“…37 Furthermore, there are hypotheses suggesting that the transfer of RNA could take place via the uptake of extracellular vesicles containing RNAs, by transcytosis from the lumen to the cytoplasm or across transmembrane RNA channels. 87 It is largely unknown, however, how efficient the gastrointestinal uptake of small molecular RNA molecules might be 78,91 and further investigations are needed to answer this crucial question.…”

Uptake and impact of natural diet-derived small RNA in invertebrates: Implications for ecology and agriculture

“…Therefore, a great deal of excitement was generated when transfer of diet-derived small RNA to ingesting organisms in a natural context was first described in the report by C-Y Zhang and colleagues, 24 which showed that dietary plant miRNAs could enter the mammalian bloodstream and regulate cholesterol metabolism through regulation of specific target mRNA in ingesting mice. Concurrently, the presence of sRNA from exogenous sources was discovered in human plasma.…”

Untitled

“…The number of miRNAs in corn, soybean seeds and rice has high sequence similarity to various animal genes. Some putative plant miRNAs could selectively package into microvesicles (MVs), which are small vesicles that are shed from almost all cell types under both normal and pathological conditions and delivered into recipient cells where the exogenous miRNAs can regulate target gene and recipient cell functions [3]. For the first time, in-vitro and in-vivo studies performed on food-derived plant miRNA, MIR168a of rice have shown that plant miRNA can pass through the mouse gastrointestinal (GI) track and enter the circulation and various organs especially the liver where it regulates mouse/human LDLRAP1 protein expression and physiological condition [3].…”