Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model.

Denisa Miklankova,Iveta Zapletalova,Irena Markova,Hana Malinska,Martin Poruba,Martina Hüttl

doi:10.3390/ijms22147680

Abstract

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids—triglycerides, cholesteryl esters and the lipotoxic intermediates—diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

Highlights

We investigated the protective effects of metformin on cardiac lipid and fatty acids (FA) metabolism and dysregulation in a prediabetic rat model: hereditary hypertriglyceridemic (HHTg) rats
While body weight was not affected in HHTg rats, relative weight of epididymal adipose tissue (EAT) significantly increased compared to Wistar controls
Hypertriglyceridemia in HHTg rats was associated with impaired glucose tolerance—non-fasting glucose, AUC0-180min and HOMA-insulin resistance (IR) were markedly elevated

Summary

Introduction

Metabolic syndrome (MS) and prediabetes are characterized by a group of disturbances associated with visceral obesity, impaired glucose signaling pathways, altered lipid metabolism, insulin resistance (IR), hypertension and hepatic steatosis [1]. The pathogenesis of these metabolic disorders is influenced by alterations in the metabolism, and the synthesis and regulation of fatty acids (FA). The hallmarks of FA alterations in MS and prediabetes are decreased long-chain polyunsaturated fatty acid (PUFA) profiles and disorders of desaturation and elongation enzymes [3] This enzyme system is involved in the regulation of whole-body metabolism, glucose and lipid metabolism, and insulin sensitivity [4].

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