Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

Kretzschmar, Tom; Wu, Jang Yen; Schulze, P. Christian

doi:10.3390/ijms22031498

Cited by 11 publications

(9 citation statements)

References 242 publications

(161 reference statements)

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“…Ceramide, DAG and NEFA are considered as lipotoxicity mediators due to their effect on heart dysfunction ( D'Souza et al, 2016 ; Kretzschmar et al, 2021 ). The levels of ceramide, DAG and NEFA in the model group were up-regulated compared with those in the sham group ( p < 0.001, p < 0.01).…”

Section: Resultsmentioning

confidence: 99%

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway

et al. 2022

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Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.

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Section: Resultsmentioning

confidence: 99%

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway

et al. 2022

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“…In the liver, free fatty acids (FFAs) go into the cytoplasm of liver cells and then into the mitochondria, aided by fatty acid transporters and carnitine palmitoyltransferase I, which act as substrates for ketogenesis, whereby the ketone bodies, β-OHB, AcAc, and acetone are produced. Thus, ketogenesis involves a metabolic pathway that produces ketone bodies, mainly in the liver [ 11 , 12 ], a process that starts with FFAs which are subsequently converted into acetyl-coenzyme A (CoA) through mitochondrial β-oxidation, which is the access point into the cycle of Krebs [ 3 ]. This occurs when lipolysis predominates over lipogenesis with a resultant rise in FFAs.…”

Section: Ketogenesis/ketolysismentioning

confidence: 99%

“…The alterations in myocardial metabolism, particularly the fatty acid β-oxidation taking place in the mitochondria and resulting in the generation of ketone bodies (ketogenesis), have always been a main focus of research in the study of the emergence and progression of heart failure (HF) and other cardiovascular (CV) diseases (CVD) [ 3 , 4 ]. During situations that lead to exhausted glucose levels in the circulation, ketone bodies produced in the liver can constitute fuel substrates for the brain, while current evidence indicates that the heart, which utilizes mainly fatty acids as an alternative fuel source, can also avail itself from ketone bodies as a fuel source [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Manolis

2023

IJMS

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The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40–70%) for ATP generation, followed mainly by glucose (20–30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4–15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

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“…This type of sphingolipid is a key component of cell membranes and is involved in numerous cellular processes such as cell proliferation, differentiation, and apoptosis. [53][54][55] Ceramide is composed of a sphingosine and a FA of varying lengths. 56 It can then be metabolized by different enzymes such as ceramidase, which hydrolyzes ceramide into sphingosine and FA, or it can be converted into other sphingolipids such as sphingomyelin or glucosylceramide.…”

Section: Compendium On Increased Risk Of Cardiovascular Complications...mentioning

confidence: 99%

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy

Nguyễn

Schulze

2023

Circulation Research

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Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.

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Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

Cited by 11 publications

References 242 publications

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy

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