RESUMEN
In response to carbohydrate deprivation or prolonged fasting the ketone bodies, ß-hydroxybutyrate (ßHB) and acetoacetate (AcAc), are produced from the incomplete ß-oxidation of fatty acids in the liver. Neither ßHB nor AcAc are well utilized for synthesis of sterols or fatty acids in human or rat liver. To study the effects of ketones on cholesterol homeostasis a novel ßHB ester (KE) ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) was synthesized and given orally to rats and humans as a partial dietary carbohydrate replacement. Rats maintained on a diet containing 30-energy % as KE with a concomitant reduction in carbohydrate had lower plasma cholesterol and mevalonate (-40 and -27 %, respectively) and in the liver had lower levels of the mevalonate precursors acetoacetyl-CoA and HMG-CoA (-33 and -54 %) compared to controls. Whole liver and membrane LDL-R as well as SREBP-2 protein levels were higher (+24, +67, and +91 %, respectively). When formulated into a beverage for human consumption subjects consuming a KE drink (30-energy %) had elevated plasma ßHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. Partial replacement of dietary carbohydrate with KE induced ketosis and altered cholesterol homeostasis in rats. In healthy individuals an elevated plasma ßHB correlated with lower plasma mevalonate.
Asunto(s)
Ácido 3-Hidroxibutírico/agonistas , Anticolesterolemiantes/administración & dosificación , Colesterol/sangre , Suplementos Dietéticos , Hidroxibutiratos/administración & dosificación , Ácido Mevalónico/antagonistas & inhibidores , Ácido 3-Hidroxibutírico/sangre , Ácido 3-Hidroxibutírico/metabolismo , Acilcoenzima A/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Adulto , Animales , Anticolesterolemiantes/metabolismo , Bebidas , Biomarcadores/sangre , Biomarcadores/química , Biomarcadores/metabolismo , Desayuno , Membrana Celular/metabolismo , Colesterol/metabolismo , Femenino , Humanos , Hidroxibutiratos/metabolismo , Hígado/metabolismo , Masculino , Ácido Mevalónico/sangre , Ácido Mevalónico/metabolismo , Ratas Sprague-Dawley , Receptores de LDL/agonistas , Receptores de LDL/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/agonistas , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Adulto JovenRESUMEN
Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of ß-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for ß-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for ß-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.