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Kinetic and physical approaches have been employed to investigate the binding of acetoacctyl-CoA to hydroxymethylglutaryl-CoA synthase. The enzyme has an apparent Km for acetoacetyl-CoA (0.35 μM) which is more than an order of magnitude tower than the Ki (6-10μM) measured for substrate inhibition by this metabolite. Hepatic acetoacetyl-CoA concentration, as measured by a sensitive and highly specific radioactive assay appears to be in the 1 -10 μM range; the concentration decreases during diabetic ketoacidosis. Total hepatic activity of hydroxymethylglutaryl-CoA synthase and levels of initochondrial enzyme protein, determined by radioimmunoassay, are not appreciably different in livers from control or ketoacidotic animals. In contrast to the decrease in hepatic acetoacetyl-CoA concentration observed during ketoacidosis, myocardial acctoacetyl-CoA levels are increased by at least tenfold when compared to controls. Elevated acetoacctyl-CoA levels may serve to inhibit fatty acid utilization by the heart. Thus, a consideration of the multiple interactions of acetoacetyl-CoA with the enzymes involved in ketone body production and utilization may be useful in evaluating the metabolic significance of this intermediate. [ABSTRACT FROM AUTHOR]

The role of ketone bodies and long-chain fatty acids in regulating myocardial content of acetoacetyl-CoA was examined in isolated perfused hearts from fed rats. Addition of 10 mM acetoacetate to a perfusion medium containing 5.5 mM glucose as exogenous substrate resulted in a sevenfold increase of cardiac acetoacetyl-CoA content. Inclusion of 0.75-0.94 mM palmitate in the perfusate did not augment the basal level of acetoacetyl-CoA nor did nit influence the already elevated content of the metabolic intermediate shown to exist in the presence of acetoacetate alone. In addition to the observed increase in myocardial acetoacetyl-CoA, a decrease in free cernitine in hearts perfused with acetoacetate was accompanied by elevated rations of both acetylcarnitine/Cernitine and long-chain fatty acylcarnitine/carnitine. Addition of palmitate in the presence of acetoacetate resulted in a further diminution of myocardial free cernitine leading to a further elevation of the long-chain fatty acylcarnitine/carnitine ratio when compared to hearts perfused with the ketone body alone. The changes in myocardial CoA and carnitine and their intermediates in hearts perfused with acetoacetate either alone or in combination with palmitate indicate that ketone bodies can divert fatty acids away from oxidation and towards esterification as triacylglycerols. Even though the interrelationships between ketones and myocardial fatty acid metabolism have not been fully characterized, a role for ketone bodies in promoting the increase in myocardial acetoacetyl-CoA found in diabetic ketoacidosis has been clearly defined. [ABSTRACT FROM AUTHOR]

Alterations in lipid metabolism were axamined in adult male Sprague-Dawley rats seven days after a single intraperitoneal injection of perfluorodecanoic acid (PFDA; 20, 40 or 80 mg/kg). Because PFDA treatment caused a dose-related reduction in feed intake, the response of vehicle-treated rats pair-fed to those receiving PFDA was monitored to distinguish direct effects of the perfluorinated fatty acid from those secondary to hypophagia. Carcass content of lipid phosphorus and free cholesterol decreased in dose-dependent fashion in both PFDA-treated and pair-fed rats. Carcass triacylglycerols diminished in a similar manner, yet PFDA-treated rats at each dose had a higher concentration of neutral acylglycerols than their vehicle-treated, pair-fed counterparts. In vehicle-treated, pair-fed rats at the 80 mg/kg dose level, lipid phosphorus and free cholesterol as a proportion of carcass fat increased, whereas the share of the triacyl-glycerols declined. Because of the higher concentration of triacylglycerols in the carcass of rats treated with 80 mg/kg PFDA, enrichment of lipid phosphorus and free cholesterol in carcass fat was less than in their pair-fed partners. The amount of lipid phosphorus and free cholesterol per hepatocyte was similar in both PFDA-treated rats and their pair-fed partners. Liver triacyl-glycerols were markedly increased in PFDA-treated rats. A similar but less extensive augmentary effect of PFDA on hepatic esterified cholesterol was found. Concentration of triacylglycerols in plasma was not elevated in PFDA-treated rats, in spite of hepatic accumulation of esterified compounds. Also, the plasma level of free fatty acids and 3-hydroxybutyrate was similar in all treatment groups, including those receiving PFDA. Thus, the administration of PFDA appears to divert fatty acids from oxidation toward esterification in the liver. [ABSTRACT FROM AUTHOR]

Relationship of Alterations in Energy Metabolism to Hypophagia in Rats Treated with 2,3,7,8-Tetrachlorodibenzo--dioxin. POTTER, C. L., MENAHAN, L. A., AND PETERSON, R. E. (1986). . 6, 89–97. Efficiency of energy utilization was evaluated temporally in 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD, 50 μg/kg)-treated male Sprague—Dawley rats (275–300 g), their pair-fed counterparts, and a group with access to ground feed. TCDD treated rats exhibited a progressive reduction in feed intake and body weight. The weight loss of vehicle-treated rats, pair-fed to the TCDD-treated group, was comparable to that found in rats receiving TCDD. Following treatment, rats administered TCDD were as efficient in absorbing feed energy from the gut as control rats. This was evidenced by similar relative digestible energy values in TCDD-treated rats, their pair-fed partners, and a group with access to feed. Equivalent decreases in oxygen consumption and carbon dioxide production in TCDD-treated rats and their pair-fed counterparts, relative to rats with access to feed, suggested that the decrease in both of these parameters in TCDD-treated rats was secondary to hypophagia and/or weight loss. Decline of respiratory quotient (RQ) to almost 0.7 in both TCDD-treated rats and their pair-fed counterparts is indicative of fat combustion. By Day 17 post-treatment, RQ increased significantly in the TCDD-treated and pair-fed groups possibly due to a limitation in the availability of lipid stores. Also, TCDD-treated rats and their pair-fed partners diminished their water intake to a similar extent without reducing urine output. Likewise, urinary excretion of both energy and urea was decreased to the same extent in rats treated with TCDD as it was in their pair-fed counterparts. However, TCDD-treated rats tended to excrete more urinary ammonia than their pair-fed partners on Days 10 and 16 post-treatment. Thus, TCDD treatment does result in a reduction of caloric intake in the rat, yet efficiency of energy utilization is preserved. [ABSTRACT FROM PUBLISHER]

1. Both glucagon (93 nM) and N6,O2'-dlibutyryl cyclic adenosine 3' : 5'-phosphate (Bu2Ado-3' : 5'-F) (10 μM) stimulated gluconeogenesis from pyruvate to the extent of 35% in the perfused liver from fasted rats Under these conditions, all of the pyruvate disappearance could be accounted form lactate and glucose. When livers were perfused with pyruvate only, a portion of the pyruvate metabolized was unaccounted for, and presumably oxidized. 2. Bu2Ado-3' : 5'-P, even in the presence of glycodiazine, stimulated gluconeogenesis from pyruvate and lowered the ratio of C3 uptake to glucose ratio, suggesting a "sparing effect" on pyruvate oxidation. 3. (+)-Decanoylcarnitine (0.5 mM) blocked a significant portion of the stimulation of gluconeogenesis by glucagon (93 nM). Other parameters of pyruvate metabolism were unaltered by the carnitine ester in the presence of glucagon. In contrast, Bu2Ado-3' : 5'-P (10 μM) in the presence of (+)-decanoylcarnitine significantly increased glucose formation in comparison to livers perfused only with the carnitine derivative. 4. Pentenoic acid (1.0 mM) resulted in a 50% inhibition of gluconeogenesis, a lowered pyruvate disappearance and an increase of pyruvate unaccounted for and presumably oxidized. Livers perfused with 4-pentenoic acid in addition to glucagon exhibited a marked suppression of gluconeogenesis, a decreased conversion of pyruvate to lactate and a lowered pyruvate disappearance rate. 5. Livers perfused with Bu2Ado-3' : 5'-P (10 μM) in addition to 4-pentenoic acid, when compared to livers perfused with 4-pentenoic acid, exhibited a significantly increased rate of gluconeogenesis. Bu2-Ado-3' : 5'-P exerted a "sparing effect" on pyruvate carbon even in the presence of 4-pentenoic acid. [ABSTRACT FROM AUTHOR]