Resveratrol and EGCG bind directly and distinctively to miR-33a and miR-122 and modulate divergently their levels in hepatic cells

Abstract

Modulation of miR-33 and miR-122 has been proposed to be a promising strategy to treat dyslipidemia and insulin resistance associated with obesity and metabolic syndrome. Interestingly, specific polyphenols reduce the levels of these mi(cro)RNAs. The aim of this study was to elucidate the effect of polyphenols of different chemical structure on miR-33a and miR-122 expression and to determine whether direct binding of the polyphenol to the mature microRNAs (miRNAs) is a plausible mechanism of modulation. The effect of two grape proanthocyanidin extracts, their fractions and pure polyphenol compounds on miRNA expression was evaluated using hepatic cell lines. Results demonstrated that the effect on miRNA expression depended on the polyphenol chemical structure. Moreover, miR-33a was repressed independently of its host-gene SREBP2. Therefore, the ability of resveratrol and epigallocatechin gallate to bind miR-33a and miR-122 was measured using 1H NMR spectroscopy. Both compounds bound miR-33a and miR-122 and differently. Interestingly, the nature of the binding of these compounds to the miRNAs was consistent with their effects on cell miRNA levels. Therefore, the specific and direct binding of polyphenols to miRNAs emerges as a new posttranscriptional mechanism by which polyphenols could modulate metabolism.

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

“…Interestingly, studies have also shown that EGCG can bind to both DNA and RNA molecules [55, 56]. Using 1 H NMR spectroscopy, one study found that EGCG modulates miR-122 and miR-33 by direct binding to the miRNAs [57]. Together these findings suggest multiple possible mechanisms by which EGCG can modulate miRNA expression.…”

Persimmon tannin alleviates hepatic steatosis in L02 cells by targeting miR-122 and miR-33b and its effects closely associated with the A type ECG dimer and EGCG dimer structural units

“…On the other hand, polyphenols may bind to miRNAs directly. Resveratrol and EGCG were shown to bind to miRNAs directly by 1 H NMR spectroscopic method (Baselga-Escudero et al, 2014). EGCG bound stronger to miR-122 than to miR-33a through an interaction with all of the rings in the molecule, while resveratrol bound equally to miR-33a and miR-122 primarily through an A ring interaction (Baselga-Escudero et al, 2014).…”

“…Resveratrol and EGCG were shown to bind to miRNAs directly by 1 H NMR spectroscopic method (Baselga-Escudero et al, 2014). EGCG bound stronger to miR-122 than to miR-33a through an interaction with all of the rings in the molecule, while resveratrol bound equally to miR-33a and miR-122 primarily through an A ring interaction (Baselga-Escudero et al, 2014). Persimmon tannin, which contained high content of EGCG and ECG in the extension units, might regulate miR-122 and miR-33b levels by direct binding, which could modulate miRNA stability or degradation.…”

A-type ECG and EGCG dimers disturb the structure of 3T3-L1 cell membrane and strongly inhibit its differentiation by targeting peroxisome proliferator-activated receptor γ with miR-27 involved mechanism

“…Some M A N U S C R I P T ACCEPTED MANUSCRIPT 19 authors suggeated that, polyphenols may bind to miRNAs directly. For example, resveratrol and EGCG were shown to bind to miRNAs directly by 1 H NMR spectroscopic method [39]. However, Lin et al [40] proposed that miR-27 might not directly repress PPARγ or C/EBPαin 3T3-L1 cells, but target an unknown gene that negatively regulates the two key transcription factors (PPARγ and C/EBPα) of adipogenic differentiation.…”

“…Current data suggested that grape proanthocyanidin extracts, EGCG [39] and cocoa proanthocyanidins [41], differed in their effects on modulating expression of miRNAs. These results and our current data suggested that the effects of polyphenols on miRNAs expression were structure-dependent.…”