Involved in lipid metabolism [172,184]. An additional miRNA which has been demonstrated to be upregulated in liver and blood of NAFLD and specifically in NASH sufferers, is miR-33 [185]. As a matter of reality, this miRNA has been suggested as a therapeutic target to manage both NAFLD and Mets, offered that it is actually deeply involved in both cholesterol and FAs metabolism, by targeting keyInt. J. Mol. Sci. 2021, 22,15 ofenzymes in cholesterol synthesis pathway (i.e., ABCA1 and ABCG1, CPT1A and AMPK), and in glucose metabolism, by inhibiting gluconeogenesis via the modulation of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC) [15155]. Similarly, miR-34a has been also shown to be upregulated in liver and serum of sufferers with NAFLD [177,18688], making it a valid and reputable biomarker capable to distinguish patients with NASH from those with NAFLD [178,189]. In vitro and in vivo research in mice observed that miR-34a specifically targets PPAR and Sirtuin 1 (SIRT1), thereby suppressing FAs catabolism and eliciting steatosis. Furthermore, miR-34a inhibition seems to improve AMP-activated protein kinase (AMPK) function, among the primary antagonist of lipogenic pathway [156]. All round, these data suggest that some dysregulated miRNAs can promote liver disease onset and progression, even though others can act in opposite way, improving defensive responses. three.3. Circular RNAs three.3.1. Circular RNAs and Obesity The first study identifying a possible function in vital molecular mechanisms in adipose tissue was published by Li and colleagues, who demonstrated that circRNA_1897 and circRNA_26852 were highly downregulated in subcutaneous tissue of massive White pigs and Laiwu pigs. Within the exact same study, authors revealed that circRNA_1897 directly targets miR-27a and miR-27b-3p, when TLR8 Agonist Purity & Documentation miR-874 and miR-486 are bound and targeted by circRNA_26852 [190]. Importantly, miR-874 and miR-486 are strongly involved in pathways linked with adipocytes differentiation and lipid metabolism [191]. Alternatively, miR-27a and miR-27b-3p are mainly involved in lipolysis and in inhibition of adipocyte differentiation via a PPAR-dependent mechanism [192]. Alongside studies performed in a number of animal models, in the final three years, various operates were published about the function of circRNAs in human adipogenesis, lipid metabolism and related disorders (Table 3). As an example, Guo and colleagues identified a strong downregulation of circ_0046367 in HepG2, an hepatoma human cell line, treated with higher concentrations of oleate and palmitate [193]. As a matter of truth, Guo et al. reported that circ_0046367 abolishes the inhibitory effect of miR-34a on PPAR, thus top to the translocation of this protein from cytoplasm to nucleus, with the consequent activation of genes involved in lipid metabolism including Cpt2 and Acbd3 [193]. One more circRNA mainly tested in RSK2 Inhibitor Gene ID oleate-stressed HepG2 cells is circHIPK3. In particulars, this circRNA enhances the lipid droplets accumulation following oleate treatment, mainly acting as miRNA sponge for miR-192-5p and consequently targeting on Foxo1 [194]. The regulation of miRNAs by circRNAs has also been demonstrated for circCDR1as on miR-7-5p. Certainly, it has been reported that circCDR1as/miR-7-5p/Wnt5 axis is capable to boost adipogenic differentiation although impairing osteogenic differentiation of Bone Marrow-derived Stem Cells (BMSCs) [195]. A further potentially crucial circRNA in obesity is circH19, which resulted upregulated in serum of pat.
