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.
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Acknowledgements
We thank Dr Daniel Wu (Yale University, USA) and Dr Zheng-Gang Liu (Cancer Research Institute, NIH, USA) for critical reading of the manuscript and discussion of data. This work was supported by grants from the National Natural Science Foundation of China (90813035, 30890044, 30771036, 30772484, 30725008, 30890032, 31071232, 31000323, and 90608010), the National Basic Research Program of China (973 Program 2006CB503909, 2007CB815701, 2007CB815703, 2007CB815705, and 2007CB815804; 863 Program 2006AA02Z177 and 2006AA10A121), and the Natural Science Foundation of Jiangsu Province (BK2008021).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Table S1
The level and sequence of plant miRNAs in human serum. (PDF 40 kb)
Supplementary information, Table S2
The level and sequence of plant miRNAs in calf serum. (PDF 37 kb)
Supplementary information, Table S3
The level of plant miRNAs in chow diet, rice, Chinese cabbage, wheat, and potato. (PDF 37 kb)
Supplementary information, Table S4
Potential mammalian genes identified as MIR168a targets. (PDF 42 kb)
Supplementary information, Table S5
The fundamental ingredients of the chow diet and fresh rice. (PDF 9 kb)
Supplementary information, Figure S1
The detection and analysis of plant miRNAs in serum samples of mammals. (PDF 116 kb)
Supplementary information, Figure S2
A quantitative analysis of plant miRNAs in mouse serum and various organs as well as the uptake of various forms of MIR168a by C57BL/6J mice. (PDF 164 kb)
Supplementary information, Figure S3
Targeting of LDLRAP1 by MIR168a. (PDF 240 kb)
Supplementary information, Figure S4
An analysis of the MIR168a levels in MVs from 293T or Caco-2 cells transfected with 20 pmol/105 MIR168a and in HepG2 cells after treatment with MVs from 293T or Caco-2 cells. (PDF 108 kb)
Supplementary information, Figure S5
The levels of MIR168a in various mouse organs after chow diet or fresh rice feeding for sustained periods (n = 8). (PDF 164 kb)
Supplementary information, Figure S6
The effects of LDLRAP1 siRNA on the levels of mouse liver LDLRAP1 and mouse plasma LDL-cholesterol, cholesterol, and triglycerides. (PDF 132 kb)
Supplementary information, Figure S7
The effects of the rice-derived MIR168a and supplemental mature miR-150 in chow diet on mouse plasma cholesterol, lipoprotein, and triglycerides and liver c-Myb protein levels. (PDF 176 kb)
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Zhang, L., Hou, D., Chen, X. et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 22, 107–126 (2012). https://doi.org/10.1038/cr.2011.158
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DOI: https://doi.org/10.1038/cr.2011.158
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