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Empagliflozin Protects Cardiac Mitochondrial Fatty Acid Metabolism in a Mouse Model of Diet-Induced Lipid Overload

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Abstract

Purpose

Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent heart failure and decrease cardiovascular mortality in patients with type 2 diabetes. Heart failure is associated with detrimental changes in energy metabolism, and the preservation of cardiac mitochondrial function is crucial for the failing heart. However, to date, there are no data to support the hypothesis that treatment with a SGLT2 inhibitor might alter mitochondrial bioenergetics in diabetic failing hearts. Thus, the aim of this study was to investigate the protective effects of empagliflozin on mitochondrial fatty acid metabolism.

Methods

Mitochondrial dysfunction was induced by 18 weeks of high-fat diet (HFD)-induced lipid overload. Empagliflozin was administered at a dose of 10 mg/kg in a chow for 18 weeks. Palmitate metabolism in vivo, cardiac mitochondrial functionality and biochemical parameters were measured.

Results

In HFD-fed mice, palmitate uptake was 1.7, 2.3, and 1.9 times lower in the heart, liver, and kidneys, respectively, compared with that of the normal chow control group. Treatment with empagliflozin increased palmitate uptake and decreased the accumulation of metabolites of incomplete fatty acid oxidation in cardiac tissues, but not other tissues, compared with those of the HFD control group. Moreover, empagliflozin treatment resulted in fully restored fatty acid oxidation pathway-dependent respiration in permeabilized cardiac fibers. Treatment with empagliflozin did not affect the biochemical parameters related to hyperglycemia or hyperlipidemia.

Conclusion

Empagliflozin treatment preserves mitochondrial fatty acid oxidation in the heart under conditions of chronic lipid overload.

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Fig. 1
Fig. 2

Abbreviations

CCCP:

Carbonyl cyanide m-chlorophenyl hydrazine

ETS:

Electron transfer system

F-pathway:

Fatty acid oxidation-dependent pathway

HFD:

High-fat diet

N-pathway:

NADH-dependent pathway

NHE:

Sodium hydrogen exchanger

OXPHOS:

Oxidative phosphorylation

ROX:

Residual oxygen consumption

SGLT2:

Sodium-glucose cotransporter 2

S-pathway:

Succinate-pathway

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Availability of Data and Materials

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

Authors were supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 857394.

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Authors and Affiliations

  1. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, 1006, Latvia

    Marina Makrecka-Kuka, Stanislava Korzh, Melita Videja, Karlis Vilks, Helena Cirule, Janis Kuka, Maija Dambrova & Edgars Liepinsh

  2. Faculty of Pharmacy, Riga Stradins University, Dzirciema 16, Riga, 1007, Latvia

    Melita Videja & Maija Dambrova

Authors
  1. Marina Makrecka-Kuka
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  2. Stanislava Korzh
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  3. Melita Videja
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  4. Karlis Vilks
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  5. Helena Cirule
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  6. Janis Kuka
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  7. Maija Dambrova
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  8. Edgars Liepinsh
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Contributions

M.M-K., M.D., and E.L. designed the research. M.M-K., S.K., M.V., K.V., H.C., and J.K. conducted experiments. M.M-K., M.D., and E.L. analyzed and interpreted the data. M.M.-K. wrote the manuscript. The study was supervised by M.M.-K., M.D., and E.L. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Marina Makrecka-Kuka.

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Conflict of Interests

The authors declare that they have no conflict of interest.

Ethics Approval and Consent to Participate

The experimental procedures involving animals were performed in accordance with the guidelines of the European Community and local laws and policies, and all of the procedures were approved by the Food and Veterinary Service, Riga, Latvia.

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Makrecka-Kuka, M., Korzh, S., Videja, M. et al. Empagliflozin Protects Cardiac Mitochondrial Fatty Acid Metabolism in a Mouse Model of Diet-Induced Lipid Overload. Cardiovasc Drugs Ther 34, 791–797 (2020). https://doi.org/10.1007/s10557-020-06989-9

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