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

Makrecka-Kūka, Marina; Korzh, Stanislava; Videja, Melita; Vilks, Kārlis; Cirule, Helena; Kuka, Janis; Dambrova, Maija; Liepinsh, Edgars

doi:10.1007/s10557-020-06989-9

Cited by 23 publications

(13 citation statements)

References 26 publications

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“…Studies have shown significant heterotopic lipid deposition in the renal tubules in DN, and empagliflozin improves lipid metabolism abnormalities in DN and other diseases. [16][17][18][19] Empagliflozin improves endothelial function, reduces atherosclerosis, and restores vascular tension in patients with type 2 diabetes. Additionally, empagliflozin relieves muscle pain and weakness and alleviates non-alcoholic fatty liver disease in patients with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

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Background: Abnormal lipid deposition in the progress of diabetic nephropathy (DN) plays an important role in a number of studies that have shown that SGLT2 inhibitor (SGLT2i) empagliflozin plays an important role in lipid metabolism, but its mechanism is still unclear. Methods: We aimed to explore the effect of empagliflozin on lipid levels in kidney cancer patients with DN and postoperative patients without DN kidney carcinoma; the patients with DN showed ectopic lipid deposition. In type 2 diabetes model mice induced by streptozotocin (STZ) and a high-fat diet, combined AMPK plus empagliflozin or empagliflozin inhibitor plus compound C was applied, followed by analyses of the blood, urine and kidney indexes to observe the correlation between SGLT2i and AMPK and lipid metabolism in diabetic kidney disease. We determined whether DN in patients with renal tubular atrophy involved lipid metabolism. Results: In clinical specimens, the adiponectin receptor AdipoR1 was reduced, and the phosphorylation acetyl-CoA carboxylase (p-ACC) was increased. In vitro and in vivo pathological immunofluorescence and Western blotting confirmed that, under the condition of high glucose, malpighian tubules displayed ectopic lipid deposition and expressed related lipid parameters accompanied by fibrosis. Empagliflozin intervention reduced lipid deposition fibrosis and renal tubular atrophy, and the addition of compound C promoted disease progression. Moreover, siAdipoR1 transfection proved that AdipoR1 affected P-AMPK and then p-ACC affected lipid metabolism in renal tubular cells. Conclusion: According to the above experimental results, empagliflozin could reduce lipid metabolism of DN through AdipoR1/P-AMPK/P-ACC pathway and delay DN progress.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Zhang¹,

Ni²,

Zha³

et al. 2021

DMSO

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“…Although controversial depending on the study setting, most agree that MI-induced failing heart leads to a decrease in fatty acid use with a corresponding increase in glucose utilization. This suggestion is supported by the growing list of others who have shown that gliflozin class drugs help to maintain the heart’s preference for utilizing fatty acids and ketone bodies [ 15 , 43 , 44 , 45 ]. However, in most cases heart failure is associated with a decrease in overall cardiac energetics [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 90%

Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis

Song

Huang

Sin

et al. 2021

IJMS

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Sodium–glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

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“…Metabolic remodeling is closely related to the occurrence and development of cardiac hypertrophy and other heart diseases. Exploring the energy metabolism mechanism of cardiomyocytes may lead to new therapeutic targets, which will be helpful to design new effective methods and strategies for the treatment of heart failure ( Bøgh et al., 2020 ; Makrecka-Kuka et al., 2020 ; Zuurbier et al., 2020 ). As we all know, physical exercise has a protective effect on the heart, and can even partially compensate for heart damage and improve heart function.…”

Section: Discussionmentioning

confidence: 99%

Energy Metabolism in Exercise-Induced Physiologic Cardiac Hypertrophy

et al. 2020

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Physiologic hypertrophy of the heart preserves or enhances systolic function without interstitial fibrosis or cell death. As a unique form of physiological stress, regular exercise training can trigger the adaptation of cardiac muscle to cause physiological hypertrophy, partly due to its ability to improve cardiac metabolism. In heart failure (HF), cardiac dysfunction is closely associated with early initiation of maladaptive metabolic remodeling. A large amount of clinical and experimental evidence shows that metabolic homeostasis plays an important role in exercise training, which is conducive to the treatment and recovery of cardiovascular diseases. Potential mechanistic targets for modulation of cardiac metabolism have become a hot topic at present. Thus, exploring the energy metabolism mechanism in exercise-induced physiologic cardiac hypertrophy may produce new therapeutic targets, which will be helpful to design novel effective strategies. In this review, we summarize the changes of myocardial metabolism (fatty acid metabolism, carbohydrate metabolism, and mitochondrial adaptation), metabolically-related signaling molecules, and probable regulatory mechanism of energy metabolism during exercise-induced physiological cardiac hypertrophy.

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

Cited by 23 publications

References 26 publications

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Empagliflozin Regulates the AdipoR1/p-AMPK/p-ACC Pathway to Alleviate Lipid Deposition in Diabetic Nephropathy

Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis

Energy Metabolism in Exercise-Induced Physiologic Cardiac Hypertrophy

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