scholarly journals Modulating fatty acid oxidation in heart failure

2011 ◽  
Vol 90 (2) ◽  
pp. 202-209 ◽  
Author(s):  
V. Lionetti ◽  
W. C. Stanley ◽  
F. A. Recchia
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

scholarly journals Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sang R. Lee ◽  
Jun H. Heo ◽  
Seong Lae Jo ◽  
Globinna Kim ◽  
Su Jung Kim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Progesterone Receptor ◽  
Fatty Acid Oxidation ◽  
Mitochondrial Respiration ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Membrane Component ◽  
Markers Of Inflammation ◽  
Receptor Membrane

AbstractObesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.

Caloric restriction limits fatty acid oxidation and improves cardiac function in heart failure associated with obesity

2018 ◽  
Vol 124 ◽  
pp. 99
Author(s):  
Qutuba G. Karwi ◽  
Liyan Zhang ◽  
Abhishek Gupta ◽  
Arata Fukushima ◽  
Vaibhav Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Caloric Restriction ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

scholarly journals Modulation of Cardiac Metabolism in Heart Failure

2019 ◽  
Vol 17 ◽  
Author(s):  
Giuseppe Rosano ◽  
Andrew Coats
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Skeletal Muscles ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Free Fatty Acid Oxidation ◽  
Capacity Modulation

Heart failure is associated with altered cardiac metabolism, in part, due to maladaptive mechanisms, in part secondary to comorbidities such as diabetes and ischaemic heart disease. The metabolic derangements taking place in heart failure are not limited to the cardiac myocytes, but extend to skeletal muscles and the vasculature causing changes that contribute to the worsening of exercise capacity. Modulation of cardiac metabolism with partial inhibition of free fatty acid oxidation has been shown to be beneficial in patients with heart failure. At the present, the bulk of evidence for this class of drugs comes from Trimetazidine. Newer compounds partially inhibiting free fatty acid oxidation or facilitating the electron transport on the mitochondrial cristae are in early phase of their clinical development.

Abstract 17036: Cardiomyocyte Krüppel-Like Factor 5 Regulates Ceramide Biosynthesis and Promotes Systolic Dysfunction in Ischemic Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Matthew K Hoffman ◽  
Ioannis Kyriazis ◽  
Dimitra Palioura ◽  
Maria Cimini ◽  
Sudarsan Rajan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
De Novo ◽  
Systolic Dysfunction ◽  
Ischemic Heart ◽  
Acid Oxidation ◽  
Ischemic Heart Failure ◽  
Specific Expression ◽  
Protein Levels

Introduction: Our lab previously showed that cardiomyocyte Krüppel-like factor (KLF)-5 regulates cardiac fatty acid oxidation. Various studies have associated heart failure with altered cardiac fatty acid oxidation and lipotoxicity. Hypothesis: Aberrant regulation of KLF5 contributes to pathophysiology and metabolic perturbations in ischemic heart failure. Methods and Results: Analysis of KLF5 mRNA and protein levels in human ischemic heart failure samples and in rodent models 2- and 4-weeks post-myocardial infarction (MI) showed significantly increased KLF5 expression. To investigate the involvement of KLF5 in the pathophysiology of ischemic heart failure, we treated mice that were subjected to MI with a pharmacological KLF5 inhibitor (ML264). ML264 increased ejection fraction and reduced diastolic volume. Likewise, mice with cardiomyocyte-specific KLF5 deletion (αMHC-KLF5 -/- mice) were protected from ischemic heart failure. Lipidomic analysis by LC-MS/MS showed that αMHC-KLF5 -/- mice after MI had lower myocardial ceramide levels compared with control mice with MI. Accordingly, the expression of cardiac SPTLC1 and SPTLC2, which regulate de novo ceramide biosynthesis, was higher in control mice with MI and lower in αMHC-KLF5 -/- mice with MI. KLF5 overexpression in HL1 cardiomyocytes increased SPTLC1 and SPTLC2 mRNA and protein levels. ChIP-qPCR and luciferase promoter assays showed that KLF5 activates the promoters of these genes via direct binding. To assess the transcriptional effects of KLF5 independent from other changes that occur with MI, we generated a mouse model of inducible (Dox-ON), cardiomyocyte-specific expression of KLF5 (αMHC-rtTA-KLF5). Systolic dysfunction was evident 2-weeks following KLF5 induction. Heart tissue from these mice exhibited increased SPTLC1 and SPTLC2 mRNA and protein levels, and inhibition of SPT using myriocin suppressed myocardial ceramide levels and alleviated systolic dysfunction. Conclusions: KLF5 is induced during the development of ischemic heart failure in humans and mice, and stimulates expression of SPTLC1 and SPTLC2 that promote ceramide biosynthesis. KLF5 inhibition emerges as a novel therapeutic target to protect against ischemic heart failure.

Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation

2014 ◽  
Vol 42 (4) ◽  
pp. 1043-1051 ◽  
Author(s):  
Osama Abo Alrob ◽  
Gary D. Lopaschuk
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Oxidative Enzymes ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

CoA (coenzyme A) and its derivatives have a critical role in regulating cardiac energy metabolism. This includes a key role as a substrate and product in the energy metabolic pathways, as well as serving as an allosteric regulator of cardiac energy metabolism. In addition, the CoA ester malonyl-CoA has an important role in regulating fatty acid oxidation, secondary to inhibiting CPT (carnitine palmitoyltransferase) 1, a key enzyme involved in mitochondrial fatty acid uptake. Alterations in malonyl-CoA synthesis by ACC (acetyl-CoA carboxylase) and degradation by MCD (malonyl-CoA decarboxylase) are important contributors to the high cardiac fatty acid oxidation rates seen in ischaemic heart disease, heart failure, obesity and diabetes. Additional control of fatty acid oxidation may also occur at the level of acetyl-CoA involvement in acetylation of mitochondrial fatty acid β-oxidative enzymes. We find that acetylation of the fatty acid β-oxidative enzymes, LCAD (long-chain acyl-CoA dehydrogenase) and β-HAD (β-hydroxyacyl-CoA dehydrogenase) is associated with an increase in activity and fatty acid oxidation in heart from obese mice with heart failure. This is associated with decreased SIRT3 (sirtuin 3) activity, an important mitochondrial deacetylase. In support of this, cardiac SIRT3 deletion increases acetylation of LCAD and β-HAD, and increases cardiac fatty acid oxidation. Acetylation of MCD is also associated with increased activity, decreases malonyl-CoA levels and an increase in fatty acid oxidation. Combined, these data suggest that malonyl-CoA and acetyl-CoA have an important role in mediating the alterations in fatty acid oxidation seen in heart failure.

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