β-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content

Stanley, William C.; Meadows, Steven R.; Kivilo, Krista M.; Roth, B. L.; Lopaschuk, Gary D.

doi:10.1152/ajpheart.00332.2003

Cited by 69 publications

(61 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The difference likely reflects higher metabolic rate in rats and the different metabolic conditions (resting vs. exercising). Using the more reliable, but very invasive, A-V balance technique, total fatty acid oxidation by pig heart was determined to be 25 nmol/g/min [23]. This is compared to the calculated rate for lean rat muscle, 10.4 nmol/g/min (assuming palmitate accounts 1/3 of all fatty acids), using the present results.…”

Section: Comparison To Other Methodsmentioning

confidence: 80%

“…As these surrogates are often discrepant from actual substrate flux, they do not reliably represent the state of fatty acid oxidation. Arterial-venous balance is also used to measure fatty acid oxidation by tissues such as heart [23] and skeletal muscle [24]. However, its application is limited by the invasiveness of catheterization across the tissue bed of interest.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

Jensen¹,

Xu²,

Zhou³

et al. 2008

Euro J Lipid Sci & Tech

View full text Add to dashboard Cite

Fatty acids are a major fuel for many tissues and abnormal utilization is implicated in diseases. However, tissue fatty acid oxidation has not been determined reliably in vivo. Furthermore, fatty acid oxidation has not been partitioned into intracellular and extracellular components. In this report, a one-pool model is described that enables direct quantitation of fluxes of intracellular and plasma fatty acids to mitochondria in skeletal muscle using dual stable isotopes and liquid chromatography/electrospray ionization ion-trap tandem mass spectrometry (LC/ESI-itMS 2 ) technology. It is validated by the determination of palmitate oxidation by skeletal muscle in lean and obese rats and the regulation by insulin. Resting postabsorptive intramyocellular and plasma palmitate oxidation by gastrocnemius muscle was determined to be 3.47±0.8 and 2.06±0.5 nmol/g min in lean and 6.96±1.8 and 1.34±0.2 nmol/g min in obese rats, respectively. In obese rats, hyperinsulinemia (1 nmol/l) suppressed intramyocellular (by 59±5% to 2.88±0.3 nmol/g min P<0.05) but not plasma (1.41±0.14 nmol/g min, P>0.05) palmitate oxidation. The fractional turnover rate of palmitoylcarnitine (0.34±0.1/min vs. 0.83±0.2/min, P<0.05) was also suppressed by insulin. In obese and lean rats, there are 83% and 51%, respectively (P=0.08), of plasma fatty acids traverse triglyceride pool before being oxidized. The results demonstrated that the methodology is feasible and sensitive to metabolic alterations and thus can be used to study fatty acid utilization at tissue level in a compartmentalized manner for the firs time.

show abstract

Section: Comparison To Other Methodsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

Jensen¹,

Xu²,

Zhou³

et al. 2008

Euro J Lipid Sci & Tech

View full text Add to dashboard Cite

show abstract

“…In perfused working rat hearts, bhydroxybutyrate supplementation inhibits pyruvate oxidation by deactivating pyruvate dehydrogenase (38), mimics insulin action (39), and competes with oxidation of FFAs (possibly also by impeding their transport into cells [40]). Within the cell, after conversion to acetoacetate (catalyzed by the mitochondrial isoform of 3-hydroxy-3-methylglutaryl-CoA synthase) and breakdown to acetyl-CoA, b-hydroxybutyrate enters the tricarboxylic acid cycle (TCA) to be oxidized.…”

Section: Rationalementioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

View full text Add to dashboard Cite

The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

show abstract

“…1) because in the diabetic heart, there is an elevated uptake and oxidation of ketone bodies (primarily ␤-hydroxybutyrate), which is concentration dependent (19,41). We assumed that the concentration of ␤-hydroxybutyrate under normal conditions is very low, and it increases with diabetes, therefore, the rate of ␤-hydroxybutyrate oxidation increases.…”

Section: Model Developmentmentioning

confidence: 99%

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Zhou

Cabrera²,

Okere³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

. Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies. Am J Physiol Heart Circ Physiol 291: H1036-H1046, 2006. First published April 21, 2006 doi:10.1152/ajpheart.01382.2005.-In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD ϩ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD ϩ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10 -15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD ϩ but had minimal effects on the mitochondrial NADH/NAD ϩ , myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD ϩ ratio that is independent of substrate supply.diabetes; exercise; heart; lactate; mitochondria; modeling CARDIAC PUMP FUNCTION is fueled by ATP hydrolysis, which is precisely matched by ATP formation, primarily in the mitochondria (42). In the transition from rest to intense exercise, there is a three-to sixfold increase in the rate of cardiac power generation, myocardial oxygen consumption (MV O 2 ), and ATP turnover (25). Nevertheless, at high work states the myocardial ATP and ADP concentrations are maintained at a relatively constant level (2, 4, 36). There is rapid activation of NADH generation in the mitochondria, flux through the electron transport chain (ETC), and ATP production by oxidative phosphorylation to match exactly ATP breakdown in the cytosol. Studies in isolated mitochondria show that the generation of NADH from carbon substrates, oxygen consumption, and oxidative phosphorylation are turned on by feedback from an increase in ADP concentration (9); however, the regul...

show abstract

β-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content

Cited by 69 publications

References 39 publications

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Contact Info

Product

Resources

About