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

¹Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970; and ²Cardiovascular Disease Research Group and Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Submitted 13 May 2003 ; accepted in final form 16 June 2003

	ABSTRACT

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This study tested the hypothesis that an acute infusion of -hydroxybutyrate inhibits myocardial fatty acid uptake and oxidation in vivo. Anesthetized pigs were untreated (n = 6) or treated with an intravenous infusion of fat emulsion (n = 7) to elevate plasma free fatty acid levels. A third group received fat emulsion plus an intravenous infusion of -hydroxybutyrate (25 µmol·kg^–1·min^–1; n = 7) for 60 min. All animals received a continuous infusion of [³H]palmitate, and myocardial fatty acid oxidation was measured from the cardiac production of ³H₂O. Plasma free fatty acid concentrations were elevated in the fat emulsion group (0.77 ± 0.11 mM) compared with the untreated group (0.15 ± 0.03 mM), which resulted in greater myocardial free fatty acid oxidation. In contrast, the group receiving -hydroxybutyrate in addition to fat emulsion had elevated -hydroxybutyrate concentration (0.87 ± 0.11 vs. 0.04 ± 0.01 mM), but suppressed fatty acid oxidation (0.053 ± 0.013 µmol·g^–1·min^–1) (P < 0.05) compared with the fat emulsion group (0.116 ± 0.029 µmol·g^–1·min^–1). There were no differences among the three groups in the tissue content for malonyl-CoA, acetyl-CoA, or free CoA or the activity of acetyl-CoA carboxylase; thus the inhibition of fatty acid oxidation by elevated -hydroxybutyrate did not appear to be due to malonyl-CoA inhibition of carnitine palmitoyl transferase-I or to an increase in the acetyl-CoA-to-free CoA ratio. In conclusion, fatty acid uptake and oxidation is blocked by an infusion of -hydroxybutyrate; this effect was not due to elevated myocardial malonyl-CoA content.

cardiac; heart; lactate; metabolism

The biochemical mechanisms responsible for inhibition of fatty acid -oxidation by ketone bodies are not well understood. Elevated rates of -hydroxybutyrate and acetatoacetate oxidation could inhibit fatty acid -oxidation by increasing the intramitochondrial acetyl-CoA-to-free CoA or NADH-to-NAD⁺ ratios, which should inhibit the ketoacyl-CoA dehydrogenase step of the fatty acid -oxidation spiral (15). Studies in isolated perfused hearts (7, 9, 14, 29), isolated myocytes (2, 12), and the in vivo swine heart (10, 32) suggest that malonyl-CoA acts as a regulator of myocardial fatty acid oxidation under a variety of physiological conditions. Malonyl-CoA is an endogenous inhibitor of CPT-I activity. Alternatively, a greater rate of ketone body oxidation could result in higher malonyl CoA production by acetyl-CoA carboxylase secondary to an increase is acetyl-CoA content, which would inhibit CPT-I and decrease fatty acid oxidation. It has been suggested that an increase in intramitochondrial acetyl-CoA content results in the transfer of acetyl units to the cytosol via carnitine acetyl transferase and carnitine acetyltranslocase and conversion back to acetyl-CoA by cytosolic carnitine acetyl transferase (7, 22, 29). Alternatively, studies (30) of skeletal muscle suggest that cytosolic acetyl-CoA could be formed by ATP-citrate lyase from citrate that has leaked out of the mitochondria. If elevated ketone body oxidation caused an increase in malonyl-CoA levels, then CPT-I activity would be inhibited, resulting in less transport of long-chain fatty acyl units into the mitochondria and a decrease in the rate of fatty acid oxidation.

In the present study, we used an in vivo swine model to test the hypothesis that an acute physiological increase in plasma ketone body levels inhibits myocardial fatty acid oxidation by increasing acetyl-CoA concentration, malonyl-CoA formation, and CPT-I inhibition and by decreasing the rate of fatty acid oxidation. Studies were carried out with an infusion of triglyceride emulsion and heparin to elevate myocardial fatty acid levels to those found with diabetes (1, 11, 31) or heart failure (19, 20, 28).

	METHODS

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Experiments were performed on anesthetized open-chest domestic swine (25–35 kg; 3.5–4 mo old). The animals were of either gender and were sexually immature. Studies were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985) and the Institutional Animal Care and Use Committee at Case Western Reserve University.

Surgical preparation. The experimental preparation has been described in detail (10, 11). Briefly, after an overnight fast, animals were sedated with an intramuscular injection of tiletamine and zolazepam (Telazol; 6 mg/kg), anesthetized with intravenous pentabarbital sodium (25 g/kg iv), intubated via a tracheostomy, and mechanically ventilated with 100% O₂ with the use of a mechanical respirator to maintain blood gases in the normal range (PO₂ > 100 mmHg, PCO₂ 30–45 mmHg, and pH 7.35–7.45). Anesthesia was maintained with a continuous infusion of pentobarbital (6–10 mg·kg^–1·h^–1 to effect). Rectal temperature was monitored and maintained near 35–37°C. A femoral artery and vein were cannulated for arterial blood withdrawal and administration of heparin, fat emulsion, and -hydroxybutyrate, respectively. The heart was exposed via a midline sternotomy as previously described (10, 11). A 5-Fr Millar Mikrotip transducer was advanced into the left ventricle (LV) through the carotid artery for determination of LV pressure. A cannula was inserted into the left atrium for microsphere injections to determine regional myocardial blood flow. A 22-gauge angiocatheter was placed in the anterior interventricular vein to collect coronary venous blood samples for analysis of myocardial oxygen consumption and -hydroxybutyrate, free fatty acid, glucose, and lactate concentrations.

Experimental protocol. Three groups of pigs were studied: untreated (n = 6), fat emulsion infusion [0.3 ml·kg^–1·h^–1 of 20% fat infusion (n = 7)] (Intralipid, Fresenius Kabi Clayton; Clayton, NC), and fat emulsion infusion + -hydroxybutyrate (25 µmol·kg^–1·min^–1 of dl--hydroxybutyrate) (Sigma; St. Louis, MO). Each group underwent an identical 40-min control period, which was followed by a 60-min treatment period. At the initiation of the control period, each animal received a continuous intravenous infusion of [9,10-³H] palmitate (30 µCi/h) for the measurement of myocardial fatty acid oxidation. Arterial and coronary venous blood was sampled after 30 and 38 min of the control period for determination of myocardial extraction of oxygen, glucose, -hydroxybutyrate, free fatty acid, and lactate. At the beginning of the treatment period, the infusions of fat emulsion and -hydroxybutyrate were started, and the fat emulsion group and the fat emulsion + -hydroxybutyrate group both received a heparin bolus (500 U/kg), followed by a continuous infusion (250 U·kg^–1·h^–1). Arterial and coronary venous blood samples were drawn at 40, 50, and 60 min of the treatment period. LV pressure was recorded immediately before each blood sample. Myocardial blood flow was measured with fluorescent microspheres (5,000,000; 15 mm diameter, Interactive Medical Technologies; Los Angeles, CA), which were injected over a 10-s period into the left atrium at 24 min of the control period and at 45 min of the treatment period. An arterial reference withdrawal sample (4 ml/min) was taken from the femoral artery for 2 min beginning 10 s before the injection of microspheres (10, 11). At the completion of each study, a transmural biopsy was obtained from the anterior free wall of the LV, rapidly freeze clamped in aluminum blocks precooled in liquid nitrogen, and stored for subsequent analysis for CoA esters and acetyl-CoA carboxylase activity. Transmural myocardial samples were also taken for measurement of tissue microspheres and divided into subendocardial, mid, and subepicardial layers (1 g each) for determination of regional myocardial blood flow (10, 11).

Analytical methods. Arterial and venous hemoglobin concentration and saturation were measured on a hemoximeter (model OSM3, Radiometer America; Cleveland, OH). Blood samples for glucose and lactate analysis were immediately deproteinized in ice-cold 6% perchloric acid [1:2 (vol:vol)], weighed, centrifuged, and analyzed in quadruplicate for glucose and triplicate for lactate, with the use of previously described enzymatic spectrophotometric methods (10, 11). Plasma free fatty acids and -hydroxybutyrate were measured using enzymatic spectrophotometric assay kits (10, 11). Plasma [³H]palmitate concentration was measured by extracting the fatty acids from 1.0 ml of plasma into 4 ml of heptane-isopropanol (3:7) and counting the organic phase as previously described (3, 27). Plasma ³H₂O concentration was measured by distillation of the water from plasma with the use of a Hickman still (Kontes) (3, 27).

Acetyl-CoA, malonyl-CoA, and free CoA were assayed with the use of HPLC separation and UV detection, as previously described (10, 11, 32). Acetyl-CoA carboxylase activity was measure as previously described (14). The myocardial concentration of fluorescent microspheres was assayed with the use of flow cytometry developed by Interactive Medical Technologies, as previously described (10, 11, 32).

Calculations. Regional myocardial blood flow was calculated with the use of the arterial reference withdrawal method (10, 11, 32). Mean transmural blood flow was calculated as the average of the subendocardial, midmyocardial, and subepicardial flows. The rate-pressure product was taken as the product of peak LV pressure and heart rate, and "efficiency index" as the rate pressure product divided by myocardial oxygen consumption. Oxygen, glucose, and lactate uptakes were taken as the product of the arterial-venous difference in blood concentration and mean transmural blood flow. The net uptake of -hydroxybutyrate and free fatty acids were calculated as the arterial venous difference in plasma concentration times the cardiac plasma flow, where plasma flow was taken as blood flow times (1 – hematocrit). The rate of fatty acid oxidation was calculated as the product of myocardial plasma flow (in ml·g^–1·min^–1) and the venous-arterial difference for [³H₂O] (dpm/ml) divided by the arterial-specific radioactivity of free fatty acids (dpm/µmol) (3, 27). The percent extraction of arterial fatty acids was calculated as 100 times the arterial-venous [³H]palmitate concentration difference divided by arterial [³H]palmitate concentration. We assumed that the uptake and oxidation of palmitate represents the oxidation of all of the major free fatty acids, as has been shown to be true in the human heart (37).

Statistics. Differences between groups were assessed with a one-way ANOVA with the use of Tukey's test to compare treatment groups. All comparisons were deemed significant at the P < 0.05 level. Values are means ± SE.

	RESULTS

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Cardiac function. Heart rate, LV peak systolic pressure, LV end-diastolic pressure, peak positive rate of developed pressure over time, myocardial blood flow, myocardial oxygen consumption, rate-pressure product, or efficiency index were not different among the three groups before the initiation of infusion (data not shown) or from 40 to 60 min of treatment (Table 1).

Substrate metabolism. During the pretreatment period, there were no differences among groups in arterial concentration, arterial-venous difference, or net uptake for glucose, lactate, or free fatty acids (data not shown). Infusion of fat emulsion or fat emulsion + -hydroxybutyrate resulted in a fivefold increase in arterial free fatty acid concentration compared with the control group (P < 0.05) (Table 2). Compared with the control group, the fat emulsion group had a fivefold increase in the free fatty acid arterial-venous difference and rate of free fatty acid uptake (Table 2). The tracer-measured free fatty acid oxidation was significantly elevated in the fat emulsion group compared with the untreated group (Fig. 1) (P < 0.05).

View larger version (14K): [in this window] [in a new window]   Fig. 1. The rate of myocardial fatty acid oxidation as measured with [3H]palmitate. *P < 0.01 compared with the untreated group; P < 0.05 compared with the fat emulsion group. -HB, -hydroxybutyrate.

The infusion of fat emulsion + -hydroxybutyrate resulted in a significant increase in the arterial concentration, arterial-venous difference, and net uptake of -hydroxybutyrate compared with the control and fat emulsion groups (Table 2). The free fatty acid concentration was not different between the fat emulsion group and the fat emulsion + -hydroxybutyrate group; however, the infusion of -hydroxybutyrate resulted in a significantly lower arterial-venous fatty acid difference and free fatty acid uptake (Table 2). The rate of fatty acid oxidation was reduced by 54% in the fat emulsion + -hydroxybutyrate group compared with the fat emulsion group (Fig. 1) (P < 0.05). The percent extraction of fatty acids was significantly reduced in the fat emulsion + -hydroxybutyrate group compared with both the untreated and fat emulsion groups (Fig. 2).

View larger version (16K): [in this window] [in a new window]   Fig. 2. Percent extraction of [3H]palmitate by the heart. *P < 0.05 compared with both the untreated and fat emulsion groups.

Arterial glucose and lactate values were not different between groups (Table 2). The arterial-venous differences and uptake for glucose and lactate were reduced by approximately one-half in the fat emulsion and the fat emulsion + -hydroxybutyrate groups compared with the untreated animals (Table 2). Thus elevation of free fatty acids inhibited glucose and lactate uptake; however, there was no further inhibition with the addition of an infusion of -hydroxybutyrate.

There were no differences between groups in the myocardial content of acetyl-CoA, malonyl-CoA, or free CoA or the ratio of acetyl-CoA to free CoA (Table 3). In addition, there were no differences between groups in the activity of acetyl-CoA carboxylase in the absence of added citrate (0.65 ± 0.06, 0.63 ± 0.06, and 0.63 ± 0.05 nmol·min^–1·mg protein^–1 for the control, fat emulsion, and fat emulsion + -hydroxybutyrate groups, respectively) or with 10 mM added citrate (1.06 ± 0.06, 1.11 ± 0.07, and 1.07 ± 0.10 nmol·min^–1·mg protein^–1, respectively).

	DISCUSSION

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The results demonstrate that an acute increase in plasma -hydroxybutyrate levels inhibits fatty acid uptake and oxidation by the heart. We saw no differences among treatment groups in the myocardial content of acetyl-CoA or malonyl-CoA or in the activity of acetyl-CoA carboxylase; thus our results do not support our hypothesis that -hydroxybutyrate decreases fatty acid oxidation by increasing malonyl-CoA formation and by inhibiting CPT-I activity. An increase in tissue acetyl-CoA content, or a fall in free CoA content, was not observed despite greater -hydroxybutyrate uptake; thus the -hydroxybutyrate-induced inhibition of fatty acid -oxidation was not due to a rise in the acetyl-CoA-to-free CoA ratio. Thus our results do not support the concept that -hydroxybutyrate inhibits myocardial fatty acid oxidation via greater malonyl-CoA inhibition of CPT-I or via an increase in the acetyl-CoA-to-free CoA ratio acting directly on fatty acid -oxidation.

The present investigation demonstrates that a moderate elevation in plasma ketone body concentration inhibits fatty acid oxidation in the normal healthy heart in vivo, which suggests that our earlier observation of low rates of fatty acid uptake in diabetic swine is due to the mild ketosis that occurs in these animals (0.8 mM plasma -hydroxybutyrate) (11). Hasselbaink et al. (13) recently showed that palmitate oxidation was significantly enhanced in isolated cardiomyocytes from streptozotocin diabetic rats in the absence of acetoacetate; however, when measurements were made with the addition of ketone bodies [either acetoacetate or -hydroxybutyrate + acetoacetate (3 mM each)], the rate of palmitate oxidation was not effected by diabetes. They also noted greater fatty acid uptake in the myocytes from diabetic rats and suggested that ketone-induced impairment of fatty acid oxidation might be responsible for the greater triglyceride storage in the heart with diabetes (6). Although the present study did not directly address the effects of diabetes on the interaction between myocardial ketone body and fatty acid metabolism, the results support the concept that elevated plasma ketone body concentration in diabetes inhibits myocardial fatty acid oxidation.

The percentage of fatty acids taken up by the myocardium that was oxidized was not different among the three treatment groups (66% in control, 75% in fat emulsion, and 71% in fat emulsion + -hydroxybutyrate). This suggests that suppression of fatty acid oxidation by ketone bodies might be mediated though inhibition of fatty acid uptake by the myocardium, and not through effects on mitochondrial oxidation. Chavez et al. (4) recently showed in the pig heart under aerobic conditions that acute inhibition of fatty acid oxidation at the mitochondrial caused a dramatic reduction in fatty oxidation (from 67% to 13%) without a significant reduction in fatty acid uptake. If ketone bodies inhibited fatty acid oxidation directly at the mitochondrial level, there should be a reduction in the rate of fatty oxidation without an immediate fall in fatty acid uptake. The observe parallel reductions in fatty acid uptake and oxidation in the present investigation suggests the possibility that a moderate elevation in ketone bodies may inhibit fatty acid entry into the cardiomyocyte and that the reduction in fatty acid oxidation results from reduced delivery of fatty acyl-CoA to the mitochondria. To our knowledge, the effect of -hydroxybutyrate and acetoacetate on the cellular fatty acid transport system has not been investigated.

We observed a decrease in the rate of uptake of glucose and lactate when free fatty acid concentrations were elevated by an infusion of triglyceride emulsion and heparin; however, there was no further decrease with the additional infusion of -hydroxybutyrate. The uptake and oxidation of glucose and lactate vary widely in the heart as a negative function of the arterial concentration of free fatty acids and ketone bodies (24, 33, 35). The classic study by Randle et al. (26) showed that cardiac carbohydrate oxidation is regulated at the level of pyruvate dehydrogenase, which is inhibited by elevated ratios of NADH to NAD⁺ and acetyl-CoA to free CoA in the mitochondria (25, 33). Oxidation of fatty acids, ketone bodies, and pyruvate all generate NADH and acetyl-CoA; thus when fatty acid and/or ketone body oxidation are high, the NADH-to-NAD⁺ and acetyl-CoA-to-free CoA ratios rise and inhibit pyruvate oxidation by the heart (23, 26). Whereas the present investigation demonstrates that the addition of elevated plasma ketone bodies on top of high free fatty acid levels does not further suppress glucose and lactate uptake, the effects of ketone bodies on pyruvate dehydrogenase activity and the NADH-to-NAD⁺ ratio have not been assessed in vivo.

In conclusion, the increase in fatty acid uptake and oxidation that occurs with elevated plasma levels of fatty acids was significantly reduced by an infusion of -hydroxybutyrate. This inhibition occurred despite no differences in the tissue content of malonyl-CoA, acetyl-CoA, or free CoA or the activity of acetyl-CoA carboxylase. Thus the inhibition of fatty acid oxidation was not due to inhibition of CPT-I or to an increase in the acetyl-CoA-to-free CoA ratio.

	DISCLOSURES

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This work was supported by National Heart, Lung, and Blood Institute Grant HL-64848, the Diabetes Association of Greater Cleveland, the Northeast Ohio Affiliate of the American Heart Association, and the Canadian Institutes for Health Research.

	ACKNOWLEDGMENTS

 
The authors thank Sara Kersey and Marisa Trenkle for technical assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: W. C. Stanley, Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106-4970 (E-mail: WCS4{at}po.cwru.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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