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

Yu Wang,Jie Li,Peiqing Liu,Cheng Chen,Jiantao Ye,Junying Huang,Heqing Huang

doi:10.1186/s12933-015-0325-x

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.

Highlights

Abnormalities in lipid and glucose metabolism are constantly observed in type 2 diabetes
Polydatin up‐regulated the protein expressions of low-density lipoprotein receptor (LDLR) and GCK but down‐regulated proprotein convertase subtilisin/kexin type 9 (PCSK9) level in palmitic acid (PA)‐induced insulin‐resistant HepG2 cells In insulin-resistant HepG2 cells, polydatin showed no cytotoxicity below 80 μM for 24 h in the MTT assay (Fig. 1a), the protein expressions of LDLR and GCK (Fig. 1b, c) were downregulated, which were obvious at the concentration of 20 μM for 24 h (P < 0.01)
We detected the protein expression of PCSK9, a protein that binds to LDLR and induces its degradation, and found that PCSK9 level was increased under the insulin-resistant conditions, which could be reversed by polydatin treatment (Fig. 1d) as expected (P < 0.001)

Summary

Introduction

Abnormalities in lipid and glucose metabolism are constantly observed in type 2 diabetes. 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. Lipid and glucose metabolism disorders are the main characteristics of insulin-resistant type 2 diabetes mellitus [1]; these disorders are the basic pathology in diabetic microvascular complications [2]. PCSK9 might be a promising target in ameliorating lipid and glucose metabolism disorders and improving insulin resistance. We found that polydatin could improve lipid and glucose metabolism in STZinduced diabetic rats and regulate GCK and LDLR expression [32]. Considering the close relationship between PCSK9 and LDLR, as well as insulin resistance, we sought to determine whether polydatin works by affecting PCSK9

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Conclusion