Meric PACs [208,279,314]. On the list of molecular mechanisms underlying the anti-lipogenic activity of PACs follows PARP3 drug precisely the same pathway as bile acids which requires the activation in the farnesoid X receptor (FXR) along with the nuclear receptor modest heterodimer partner (NR0B2/SHP) [282,294]. Far more especially, PACs, too as BA, are in a position to bind to and activate FXR, therefore inducing the expression of its target SHP, which, in turn, regulates theAntioxidants 2021, 10,33 ofexpression of many lipogenic genes like SREBP-1c, CPT-1a and apolipoprotein A5 (ApoA5). FXR or SHP suppression via siRNA or knockout entirely abolished the TG-lowering action of GSPE both in vitro and in vivo, confirming their crucial role as mediators from the hypotriglyceridemic actions of PACs [282,283]. Additionally, a attainable interaction of PACs using the transcription aspect EB (TFEB) was also highlighted. Procyanidin B2, in all probability by means of direct interaction with TFEB, modulates its activity and consequently the expression of its target genes (Lamp1, Mcoln, Uvrag) involved in the lysosomal pathway in HFD-induced liver Raf Accession steatosis [314]. These final results could identify procyanidin B2 as a promising candidate for the prevention and treatment of NAFLD. PAC hypolipidemic effect is further enhanced thanks to an active function in microRNA regulation (miR). In particular, PACs were shown to rapidly and transiently repress miR-33, which targets ATP-binding cassette A1 (abca1) and genes involved within the modulation of fatty acid and cholesterol homeostasis, and miR-122, which targets fatty acid synthesis genes (e.g., srebp-1c, fas) and fatty acid -oxidation genes (e.g., NADPH-cytochrome P450 reductase-1, ppar-/) [288,293,317,318]. Their deregulation has been related with metabolic issues like obesity and MetS. A correlation of miR-33 and miR-122 levels with lipemia in nutritional rat models, hepatic and peripheral blood mononuclear cell lines (PBMCs) has been established [288]. Their sustained overexpression in dyslipidemia conditions is neutralized by long-term supplementation with GSPE [288,293]. Furthermore, GSPE attenuates the high-fat diet-induced overexpression of miR-96 and, consequently, of its downstream molecules which include FOXO1, mTOR, p-mTOR, and LC3A/B, which are known for enhancing the autophagic flux for clearance of lipid accumulation [295]. Going into far more detail around the molecules accountable for this miR inhibition, it has been shown that A-type ECG and EGCG dimers especially ameliorate hepatic steatosis drastically lowering lipid accumulation in L02 cells via the regulation of miR-122 and miR-33b and their target genes [318]. Even so, the exact molecular mechanism by which PACs could impact miRs regulation has not but been completely elucidated: it could underlie the binding to elements involved in miRs biogenesis or, alternatively, the direct binding of PACs to miRs to modulate their stability or degradation. Other signaling pathways influenced by PACs involve cholesterol metabolism and catabolism. Below high fat intake, procyanidin B2 from Annurca apples reduces cholesterol synthesis by diverting citrate and acetyl-CoA towards the Krebs cycle [319]. Concomitantly, it lowers fatty acid synthesis and promotes lipolysis and fatty acid -oxidation thanks to a enhance in mitochondrial activity [319]. In addition, enhanced cholesterol degradation and excretion contribute to the cholesterol-lowering impact of PACs: GSPE causes a considerable lower in plasma TC and TAG levels in h.