In our experiment, the weight gain, plasma lipid levels and liver pathology of high fat/high cholesterol diet mice had a favorable shift after 8 weeks aerobic exercise. And we think one of the mechanisms by which aerobic exercise improved hyperlipidemia was to up-regulate the expression of miR-21a-5p, thus inhibited the expression of target genes FABP7, HMGCR, ACAT1 and OLR1, which were closely related to lipid metabolism.
MiR-21a-5p plays a key role in suppressing the occurrence and development of hyperlipidemia, we have shown that the expression of miR-21a-5p had a significant reduction in hyperlipidemia mice, and inhibition of miR-21a-5p would expect to result in a disorder of lipid metabolism. Whereas, the opposite was observed after aerobic exercise intervention. Recent studies have demonstrated that exercise improves non-alcoholic fatty liver disease, atherosclerosis, cancer and other diseases by regulating miRNAs. Xiao J. J et al provided compelling evidence suggesting that miR-212 might be a novel therapeutic target mimicking the benefit of exercise in the treatment of NAFLD14. In addition, aerobic exercise and statins can induce the expression of miR-146a, thereby reducing the TRAF and TLR4 signaling pathways and vascular inflammatory damage in atherosclerosis, confirming the protective effect of aerobic exercise on vascular diseases15. Furthermore, exercise could effectively reduce the tumor volume, lower levels of proinflammatory cytokines TNFα, increase the anti-inflammatory cytokine IL-10 by regulating miR-21a-5p expression16. Taken together, these researches indicated that aerobic exercise could play a variety of physiological regulatory roles through miRNA, and miR-21a-5p is an important target for exercise to improve lipid metabolism.
As we all know Dicer1 is essential for miRNA maturation, the disruption of the Dicer1 results in the loss of mature miRNAs. Ming-xia LIU et al. have shown that the expression of Dicer1 was significantly reduced in NASH mice model and inversely associated with hepatic FC level. Through further research they found that serum lipid disorder caused by Dicer1 deletion may be due to the decreased expression of miR-29, which improve nonalcoholic fatty liver disease by suppressing HMGCR expression17. This study made us wonder aerobic exercise increased the expression of miR-21a-5p may be through the enhancement of Dicer1 expression. Interestingly, Aaron P Russell et al. have found that after 60 min acute endurance exercise, miRNA processing complex, including Drosha, Dicer and Exportin-5, were significantly up-regulated by 35, 35 and 30%, respectively18. And our study also showed that Dicer1 expression decreased in the HH group, while increased after exercise intervention, which may be one of the reasons why exercise promoted miR-21a-5p expression.
Researches on mechanism of miRNAs regulate target gene expression are generally believed that miRNA is to induce post-transcriptional gene silencing through mRNA degradation or translation repression. Mihnea et al summarized seven unconventional ways in which miRNAs can exert regulatory functions19, and recently the function of miRNA has been extended to transcriptional levels, either directly or indirectly20. In our study, the expression of FABP7, HMGCR, ACAT1 and OLR1 were increased in miR-21a-5p KD mice, indicated that miR-21a-5p played a negative regulatory role on these target genes, whether this negative regulatory effect is at the post-transcriptional level or at the transcriptional level still needs further in-depth study. Importantly, recent studies have indicated that miRNAs have a dual role. When it is located in the cytoplasm, miRNAs inhibit gene expression, when it is in the nucleus, it can activate gene expression by binding to the target gene enhancer21. If the miRNA is distributed in both the cytoplasm and the nucleus, then it is likely to perform multiple functions on the target genes. And researches have revealed that miR-21a-5p could be detected both in the cytosol and in the nucleus22, so we will pay more attention to how miR-21a-5p regulates the expression of target genes in the nucleus in the future.
In addition, in our study, it was found that there was no significant change in PTEN and PPARα in miR-21a-5p KD mice, the result might reflect a compensatory mechanism of the organism under the stimulation of pathological stress of dyslipidemia after miR-21a-5p knockdown. Then, we thought that there may be other pathways were implicated in the regulation of aerobic exercise on the expression of PTEN and PPARα other than miR-21a-5p23.
In conclusion, this study provided new insights into the mechanism of aerobic exercise regulated lipid metabolism through miRNA. Our work identified miR-21a-5p as a potential regulator of aerobic exercise affecting lipid metabolism, achieved the favorable goal in hyperlipidemia by synergistically inhibiting the expression of target genes FABP7, HMGCR, ACAT1, and OLR1.