The association of meldonium-induced liver steatosis with alterations in fatty acid metabolism

Metabolic associated fatty liver disease (MAFLD) is one of the most prevalent chronic liver diseases, with a rising incidence worldwide. In 2024, The Food and Drug Administration in the US approved resmetirom, a liver-targeted thyroid hormone receptor beta-selective agonist for the treatment of non-cirrhotic MAFLD with moderate to advanced fibrosis. While this approval marks a nig step forward, the accumulation of liver fat remains a substantial risk factor for progression to steatosis and liver failure.

Fat accumulation in the liver stems from an imbalance between fatty acid (FA) uptake, synthesis and disposal. In addition to reduced mitochondrial FA β-oxidation and potentially increased hepatic FA synthesis, elevated delivery and transport of free FAs into the liver are critical to the pathogenesis of MAFLD.

In view of that, in a recent study published in the KeAi journal Liver Research, a team of researchers from Norway investigated how diminished mitochondrial FA β-oxidation affects FA composition and estimated elongase and desaturase activities by incorporating meldonium into a high-carbohydrate diet.

“We found that tetradecylthioacetic acid (TTA) effectively mitigates meldonium-induced steatosis in mice on a high-carbohydrate diet,” shares Rolf K Berge, senior and co-corresponding author of the study. “TTA not only reverses the alterations in delta-6 desaturase (D6D) activity and fatty acid (FA) elongation caused by meldonium, but also alleviates the depletion of plasma L-carnitine and acylcarnitines while promoting peroxisomal β-oxidation.”

Notably, TTA prevents steatosis by counteracting meldonium-induced changes in FA synthesis and elongation, particularly through D6D inhibition, which is linked to hepatic steatosis.

Lise Madsen, the other corresponding, pointed out an expected finding. “Increased de novo FA synthesis did not contribute to meldonium-induced steatosis. Instead, alterations in FA elongation and desaturation play a more critical role in liver fat accumulation,” she says.  

In particular, TTA can reduce meldonium-induced triglyceride levels by 80% and restore both D6D and elongase activities. Additionally, the relative proportions of C18:4n-3 and C18:3n-6 in plasma may serve as potential biomarkers for hepatic steatosis, while circulating levels of γ-linolenic acid, along with estimated D6D and n-6 elongase indexes, could provide valuable prognostic markers for fatty liver development.

Contact author: Lise Madsen, Department of Clinical Medicine, University of Bergen, Bergen, Norway. E-mail:lise.madsen@uib.no

Funder: The animal work was performed at The laboratory Animal Facility, a code facility at University of Bergen.

Conflict of interest: The authors declare that they have no conflict of interest.

See the article: Bodil, B., et al., Meldonium-induced steatosis is associated with increased delta 6 desaturation and reduced elongation of n-6 polyunsaturated fatty acids, Liver Research, Volume 8, Issue 3, 2024, Pages  152-164, https://doi.org/10.1016/j.livres.2024.09.001.