Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9)

Abstract

BackgroundAbnormalities in lipid and glucose metabolism are constantly observed in type 2 diabetes. However, these abnormalities can be ameliorated by polydatin. Considering the important role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in metabolic diseases, we explore the possible mechanism of polydatin on lipid and glucose metabolism through its effects on PCSK9.MethodsAn insulin-resistant HepG2 cell model induced by palmitic acid (PA) and a db/db mice model were used to clarify the role of polydatin on lipid and glucose metabolism.ResultsIn insulin-resistant HepG2 cells, polydatin upregulated the protein levels of LDLR and GCK but repressed PCSK9 protein expression, besides, polydatin also inhibited the combination between PCSK9 and LDLR. Knockdown and overexpression experiments indicated that polydatin regulated LDLR and GCK expressions through PCSK9. In the db/db mice model, we found that polydatin markedly enhanced GCK and LDLR protein levels, and inhibited PCSK9 expression in the liver. Molecular docking assay was further performed to analyze the possible binding mode between polydatin and the PCSK9 crystal structure (PDB code: 2p4e), which indicated that steady hydrogen bonds formed between polydatin and PCSK9.ConclusionsOur study indicates that polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating PCSK9.

Polydatin Improves Glucose and Lipid Metabolisms in Insulin-Resistant HepG2 Cells through the AMPK Pathway

“…39) Proprotein convertase subtilisin/kexin type-9 (PCSK9) can bind to LDLR as a molecular chaperone to generate LDLR degradation. 40) As our results suggest, this may be because polydatin can increase LDLR by downregulating PCSK9. 41) In summary, we found that polydatin increased AMPK activation, increased phosphorylated AMPK, Akt, GSK-3β, and ACC, while decreasing nuclear protein levels of SREBP-1c and increasing LDLR expression.…”

“…40) As our results suggest, this may be because polydatin can increase LDLR by downregulating PCSK9. 41) In summary, we found that polydatin increased AMPK activation, increased phosphorylated AMPK, Akt, GSK-3β, and ACC, while decreasing nuclear protein levels of SREBP-1c and increasing LDLR expression. These results indicated that polydatin can protect the glucose metabolism by increasing phosphorylated AMPK, Akt, and GSK-3β, as well as increasing the production of hepatic glycogen to regulate blood glucose.…”

BIOLOGICALLY ACTIVE COMPOUNDS OF KNOTWEED (Reynoutria spp.)

“…The effect of polydatin on increased Akt phosphorylation is independent of prompting insulin secretion, but dependent of increasing IRS phosphorylation. The study of Wang et al [73] indicates that polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9). Polydatin has important therapeutic effects on metabolic syndrome [74].…”

A New Strategy for Rapidly Screening Natural Inhibitors Targeting the PCSK9/LDLR Interaction In Vitro

“…Herbal medicines are widely used for the treatment of hypercholesterolemia, and some natural products have been reported to regulate the transcription and expression of PCSK9 because of their cholesterol-lowering effects [ 10 , 11 , 12 , 13 ]. However, only a few natural products in either extracts or individual chemicals have been explored for interrupting the PCSK9/LDLR interaction directly.…”

“…The ratio of the tags (GST/His) could then be used for evaluating the inhibitory activities. Natural products with cholesterol-lowering effects, such as polydatin ( 1 ) [ 10 , 20 ], tetrahydroxy- diphenylethylene-2- O -glucoside ( 2 ) [ 21 ] and crocin I ( 3 ) [ 22 ], were selected as the candidates for screening the potential natural inhibitors targeting the PCSK9/LDLR interaction. A cell assay was also conducted for further verification.…”