A fatty acid analogue targeting mitochondria exerts a plasma triacylglycerol lowering effect in rats with impaired carnitine biosynthesis.

Carine Lindquist,Seth Hallström,Rolf Kristian Berge,Asbjørn Svardal,Bodil Bjørndal,Christine Renate Rossmann,Catherine Mounier

doi:10.1371/journal.pone.0194978

Abstract

L-carnitine is important for the catabolism of long-chain fatty acids in the mitochondria. We investigated how the triacylglycerol (TAG)-lowering drug 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) influenced lipid metabolism in carnitine-depleted, 3-(2,2,2-trimethylhydrazinium)propionate dehydrate (Mildronate; meldonium)-treated male Wistar rats. As indicated, carnitine biosynthesis was impaired by Mildronate. However, TAG levels of both plasma and liver were decreased by 1-triple TTA in Mildronate-treated animals. This was accompanied by increased gene expression of proteins involved in mitochondrial activity and proliferation and reduced mRNA levels of Dgat2, ApoB and ApoCIII in liver. The hepatic energy state was reduced in the group of Mildronate and 1-triple TTA as reflected by increased AMP/ATP ratio, reduced energy charge and induced gene expression of uncoupling proteins 2 and 3. The increase in mitochondrial fatty acid oxidation was observed despite low plasma carnitine levels, and was linked to strongly induced gene expression of carnitine acetyltransferase, translocase and carnitine transporter, suggesting an efficient carnitine turnover. The present data suggest that the plasma TAG-lowering effect of 1-triple TTA in Mildronate-treated rats is not only due to increased mitochondrial fatty acid oxidation reflected by increased mitochondrial biogenesis, but also to changes in plasma clearance and reduced TAG biosynthesis.

Highlights

One of the risk factors characterizing the metabolic syndrome is dyslipidemia, including increased plasma triacylglycerol (TAG) [1]
Metabolic syndrome is associated with increased cardiovascular risk [2,3,4,5], in which cardiovascular disease is the main cause of death worldwide [6]
Rats were given a daily dose of either Mildronate or Mildronate in combination with an artificial fatty acid 1-triple TTA, earlier shown to increase β-oxidation and mitochondrial proliferation

Summary

Introduction

One of the risk factors characterizing the metabolic syndrome is dyslipidemia, including increased plasma triacylglycerol (TAG) [1]. Metabolic syndrome is associated with increased cardiovascular risk [2,3,4,5], in which cardiovascular disease is the main cause of death worldwide [6]. Non-alcoholic fatty liver disease is defined as accumulation of lipids in the liver, associated with dyslipidemia [7], and is discussed to either be the hepatic manifestation of metabolic syndrome or an independent cardiovascular risk factor [8]. Non-alcoholic fatty liver disease is referred to as a mitochondrial disease, including dysfunctional mitochondrial fatty acid oxidation and biogenesis [11, 12], drugs that target mitochondrial function can potentially improve both fatty liver disease and plasma TAG

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