Defective lipid metabolism is associated with increased risk of various chronic diseases, such as obesity, cardiovascular diseases, and diabetes. Resveratrol (RSV), a natural polyphenol, has been shown the potential of ameliorating disregulations of lipid metabolism. The objective of this study was to investigate the effects of feed intake and RSV on lipid metabolism in zebrafish (Danio rerio). The adult males were randomly allocated to 6 groups: control (Con, 8 mg cysts/fish/day), control with 20 μmol/L RSV (Con+RSV), calorie restriction (CR, 5 mg cysts/fish/day), calorie restriction with RSV (CR+RSV), overfeed (OF, 60 mg cysts/fish/day), and overfeed with RSV (OF+RSV) groups. The treatment period was 8 weeks. Results showed that CR reduced body length, body weight, and condition factor of zebrafish. CR reduced levels of plasma triglyceride (TG) and induced protein expression of phosphorylated AMP-activated protein kinase-α (pAMPKα), silent information regulator 2 homolog 1 (Sirt1), and peroxisome proliferator activated receptor gamma coactivator-1α (PGC1α). RSV attenuated CR-induced pAMPKα/AMPKαincreases. RSV increased levels of Sirt1 protein in the OF zebrafish, and decreased OF-induced increase in peroxisome proliferator-activated receptor-γ (PPARγ) protein level. Additionally, RSV down-regulated caveolin-1 and up-regulated microtubule-associated protein 1 light chain 3 -II (LC3-II) protein levels in OF zebrafish. In conclusion, these results suggest that 1) CR reduces plasma TG level through activation of the AMPKα-Sirt1- PGC1α pathway; 2) under different dietary stress conditions RSV might regulate AMPK phosphorylation bi-directionally; 3) RSV might regulate lipid metabolism through the AMPKα-Sirt1-PPARγ pathway in OF zebrafish.
Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.
Epidemiological and experimental studies reveal that Western dietary patterns contribute to chronic kidney disease, whereas dietary restriction (DR) or dietary polyphenols such as green tea polyphenols (GTPs) can ameliorate the progression of kidney injury. This study aimed to investigate the renal protective effects of GTPs and explore the underlying mechanisms. Sixty Wistar rats were randomly divided into 6 groups: standard diet (STD), DR, high-fat diet (HFD), and three diets plus 200 mg/kg(bw)/day GTPs, respectively. After 18 weeks, HFD group exhibited renal injuries by increased serum cystatin C levels and urinary N-acetyl-β-d-glucosaminidase activity, which can be ameliorated by GTPs. Meanwhile, autophagy impairment as denoted by autophagy-lysosome related proteins, including LC3-II, Beclin-1, p62, cathepsin B, cathepsin D and LAMP-1, was observed in HFD group, whereas DR or GTPs promoted renal autophagy activities and GTPs ameliorated HFD-induced autophagy impairment. In vitro, autophagy flux suppression was detected in palmitic acid (PA)-treated human proximal tubular epithelial cells (HK-2), which was ameliorated by epigallocatechin-3-gallate (EGCG). Furthermore, GTPs (or EGCG) elevated phosphorylation of AMP-activated protein kinase in the kidneys of HFD-treated rats and in PA-treated HK-2 cells. These findings revealed that GTPs mimic the effects of DR to induce autophagy and exert a renal protective effect by alleviating HFD-induced autophagy suppression.
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