18:0 Lyso PC, a natural product with potential PPAR-γ agonistic activity, plays hypoglycemic effect with lower liver toxicity and cardiotoxicity in db/db mice

https://doi.org/10.1016/j.bbrc.2021.09.059Get rights and content
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Highlights

  • An in-house natural products library containing 8,545 compounds for virtual screening.

  • An unreported natural lipid compound, 18:0 Lyso PC, is an agonist of PPAR-γ.

  • 18:0 Lyso PC showed similar hypoglycemic and lipid-lowering effects compared with rosiglitazone.

  • 18:0 Lyso PC elicits markedly fewer adverse reactions than rosiglitazone in db/db mice.

Abstract

Rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), displays a robust hypoglycemic action in patients with type 2 diabetes mellitus (T2DM) and elicits serious adverse reactions, especially hepatotoxicity and cardiotoxicity. Here, we aims to find a new natural PPAR-γ agonist with less adverse reactions than rosiglitazone in db/db mice. The method of virtual screening was used to identify a PPAR-γ agonist 18:0 Lyso PC from an in-house natural product library. We verified its pharmacological effects and adverse reactions comparing with rosiglitazone in vivo and in vitro. 18:0 Lyso PC exhibited pharmacological effects similar to those of rosiglitazone in db/db mice. Moreover, 18:0 Lyso PC showed a lower extent of liver injury and cardiotoxicity in db/db mice. The mechanism, by which this natural compound alleviates metabolic syndrome, involves a reduction in fatty acid synthesis mediated by activation of the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase-alpha (AMPKα) and acetyl-CoA carboxylase (ACC) and an increase expression of uncoupled protein 1 (UCP1) and PPAR-γ coactivator-1 alpha (PGC1-α). 18:0 Lyso PC, a natural compound, can show a similar hypoglycemic effect to rosiglitazone by activating PPAR-γ, while eliciting markedly fewer adverse reactions than rosiglitazone.

Keywords

T2DM
18:0 Lyso PC
Cardiotoxicity
Liver injury
Rosiglitazone

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These authors contributed equally to this work.