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

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.

Meldonium: Pharmacological, toxicological, and analytical aspects

“…The study demonstrated that meldonium increased PGC-1 expression, which showed reduced symptoms of HD, alleviating motor dysfunction. 54 Meldonium also demonstrated reduction of oxidative stress levels in brain tissues, 54 while Lindquist et al 55 showed an increase in the expression of genes linked with the reduction of reactive oxygen species. 55 Based on the literature findings (Table 2), betaoxidation inhibition, lipid metabolism modulation, and consequently the beneficial cardiac effects require at least 10 days of meldonium administration in ICR mice.…”

“…54 Meldonium also demonstrated reduction of oxidative stress levels in brain tissues, 54 while Lindquist et al 55 showed an increase in the expression of genes linked with the reduction of reactive oxygen species. 55 Based on the literature findings (Table 2), betaoxidation inhibition, lipid metabolism modulation, and consequently the beneficial cardiac effects require at least 10 days of meldonium administration in ICR mice. 29,40 However, cerebral and vasodilatory effects are pronounced less than 1 h after intraperitoneal administration in Wistar rats.…”

“…54 Meldonium also demonstrated reduction of oxidative stress levels in brain tissues, 54 while Lindquist et al 55 showed an increase in the expression of genes linked with the reduction of reactive oxygen species. 55…”

Mitochondrial metabolomic profiling for elucidating the alleviating potential of Polygonatum kingianum against high-fat diet-induced nonalcoholic fatty liver disease

“…Non-alcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is characterized by the accumulation of lipids in the liver, and it can progress to inflammatory non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma and eventually culminate in liver failure[1,2]. Apart from dieting and regular exercising, no other treatment is recommended for NAFLD[3].…”

The Influence of Metabolic Therapy on Clinical and Hemodynamic Parameters in Patients With Stable Angina

“…The mechanism of meldonium is well understood; being a partial inhibitor of fatty acids oxidation and an analog structurally to the precursor of the gamma-butyrobetaine (GBB) (4). It inhibits carnitine metabolism and biosynthesis by competing with GBB hyrdroxylase enzyme, that catalyzes the last step in carnitine biosynthesis pathway, also inhibiting kidneys' reabsorbtion (5). Meldonium's other effect is the inhibition the long chain fatty acids transportation through the mitochondrial membranes.…”