Milk’s Role as an Epigenetic Regulator in Health and Disease
Abstract
:1. Introduction
2. Extracellular Vesicles: Signalosomes for Intercellular Communication
3. Milk Exosomes: Long-Distance Transmitters of Lactation-Specific miRNAs
3.1. Stability of Milk Exosomal miRNAs
3.2. Milk Exosome Uptake
3.3. Milk’s Exosomal miRNAs
4. Epigenetic Regulation of Lactation
5. DNMT-Targeting miRNAs of Milk: Activators of the Recipient’s Epigenome
6. Activation of Developmental Genes via DNA CpG Demethylation
6.1. FTO
6.2. NRF2
6.3. INS
6.4. IGF1
6.5. CAV1
6.6. FOXP3
6.7. NRA4
6.8. NFKBI
6.9. LCT
7. Appetite Control and Feeding Reward
8. Intestinal Growth
9. Adipogenesis
10. Myogenesis
11. Osteogenesis
12. Epidermal Differentiation
13. Milk-Mediated Epigenetic Signaling and Diseases of Civilization
13.1. Obesity
13.2. Type 2 Diabetes Mellitus
13.3. Cancer
13.4. Neurodegenerative Diseases
13.4.1. Alzheimer’s Disease
13.4.2. Parkinson’s Disease
14. Metformin
15. Enhancement of Dairy Milk Yield: A Potential Health Hazard
16. Future Prospects and Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
References
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The majority of milk exosomes is secreted by mammary epithelial cells | [14] |
Milk exsomes resist intestinal degradation | [38,40,43,61,62,66] |
Milk exosomes are taken up by intestinal epithelial cells | [75,76,77] |
Milk exosomes are taken up by vascular endothelial cells | [78] |
Increased serum levels of milk-derived miRNAs during lactation | [41,46] |
Dose-dependent increase of miRNA-29b and miRNA-200c in the serum of cow’s milk consumers | [79] |
Increase of miRNA-29b and miRNA-200c in peripheral blood mononuclear cells of human volunteers 6 h after commercial milk intake | [79] |
Increased expression of RUNX2, a regulatory target of miRNA-29b, in PBMCs of healthy humans after cow’s milk consumption | [79] |
Detection of bovine milk exosomes in murine splenocytes | [75] |
Predicted role of milk miRNAs in organismal development and organ maturation | [17,80,81] |
Human miRNAs Targeting DNMTs | Bovine miRNAs Targeting DNMTs |
---|---|
hsa-miRNA-148a-5p 6-aaaguucugagacacuccgacu-27 hsa-miRNA-148a-3p 44-ucagugcacuacagaacuuugu-65 | bta-miRNA-148a-3p 44-ucagugcacuacagaacuuugu-65 |
hsa-miRNA-21-5p 8-uagcuuaucagacugauguuga-29 hsa-miRNA-21-3p 46-caacaccagucgaugggcugu-66 | bta-miRNA-21-5p 8-uagcuuaucagacugauguugacu-31 bta-miRNA-21-3p 47-aacagcagucgaugggcugucu-68 |
hsa-miRNA-29b-1-5p 10-gcugguuucauauggugguuuaga-33 hsa-miRNA-29b-1-3p 51-uagcaccauuugaaaucaguguu-73 | bta-miRNA-29-1-3p 51-uagcaccauuugaaaucaguguu-73 |
mRNA | Function | References |
---|---|---|
RUNX1T1 | Promotion of adipogenesis, mitotic clonal expansion increasing adipocyte numbers | [152,247] |
PPARγ | Promotion of adipogenesis | [248] |
CEBPα | Promotion of adipogenesis | [248] |
PGC1α | Promotion of adipogenesis | [249] |
Ghrelin | Increased ghrelin mRNA and protein expression, increased orexigenic signaling | [228] |
Dopamine receptor 2 and 3 | Increased dopaminergic signaling potentially involved in feeding reward | [239] |
Target | Reported Biological Effects of miRNA-148a | References |
---|---|---|
DNMT1 | Reduced maintenance DNA methylation during cell division | [118,244] |
DNMT3B | Reduced de novo DNA methylation | [121] |
ABCA1 | Reduced reverse cholesterol transport, risk of dyslipidemia | [106] |
LDLR | Reduced hepatic uptake of LDL, risk of dyslipidemia | [106] |
CPT1A | Reduced mitochondrial fatty acid β-oxidation, risk of dyslipidemia | [106] |
MIG6 | Reduced inhibition of EGFR, increased cell proliferation | [278] |
ROCK1 | Reduced suppression of myogenesis, enhanced myogenesis | [261] |
Gene | Functions | References |
---|---|---|
FTO | Increased RNA m6A demethylation, resulting in increased transcription, generation of adipogenic splice variant (short form) of RUNX1T1 | [152,154,155,156] |
INS | Increased insulin expression, activation of mTORC1, increased glucose uptake, anabolism | [170] |
IGF1 | Increased IGF-1 expression, activation of mTORC1, promotion of growth and GH signaling | [174,175] |
CAV1 | Stimulation of insulin- and IGF-1 receptor signal transduction, promotion of adipocyte differentiation | [179] |
FABP4 | Adipogenic differentiation | [243] |
LPL | Adipogenic differentiation | [243] |
NRF2 | Increased expression of mTOR, RagD, promotion of mTORC1 signaling, promotion of osteogenesis | [162,163,164,165,166] |
NR4A3 | Promotion of myogenesis and FoxP3 expression | [201,202,207,253] |
FOXP3 | Increased FoxP3 expression, differentiation and stable expression of regulatory T cells, induction of immune tolerance, prevention of allergy | [183,184,185,186,187] |
APOE | Decreased isotype-specific APOE methylation in brains of patients with Alzheimer’s disease | [372] |
SNCA | Decreased methylation at SNCA intron 1 in patients with Parkinson’s disease | [383,384] |
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Melnik, B.C.; Schmitz, G. Milk’s Role as an Epigenetic Regulator in Health and Disease. Diseases 2017, 5, 12. https://doi.org/10.3390/diseases5010012
Melnik BC, Schmitz G. Milk’s Role as an Epigenetic Regulator in Health and Disease. Diseases. 2017; 5(1):12. https://doi.org/10.3390/diseases5010012
Chicago/Turabian StyleMelnik, Bodo C., and Gerd Schmitz. 2017. "Milk’s Role as an Epigenetic Regulator in Health and Disease" Diseases 5, no. 1: 12. https://doi.org/10.3390/diseases5010012
APA StyleMelnik, B. C., & Schmitz, G. (2017). Milk’s Role as an Epigenetic Regulator in Health and Disease. Diseases, 5(1), 12. https://doi.org/10.3390/diseases5010012