An Ester of β‐Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans

Abstract

In response to carbohydrate deprivation or prolonged fasting the ketone bodies, β-hydroxybutyrate (βHB) and acetoacetate (AcAc), are produced from the incomplete β-oxidation of fatty acids in the liver. Neither βHB 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 βHB 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 βHB 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 βHB correlated with lower plasma mevalonate.

Novel ketone diet enhances physical and cognitive performance

“…( R )‐3‐Hydroxybutyl ( R )‐3‐hydroxybutyrate has been shown to have antilipidemic effects in rats and humans (40) and to increase mitochondrial biogenesis and UCP1 expression in brown adipose tissue of mice (41), aswell as to decrease appetite in rats and mice (39, 41). As a precaution against possible palatability issues or appetitesuppression effects associated with ketone ester feeding, rats that were allocated to the carbohydrate and Western diets in this study were pair fed, receiving the same calories each day as their ketone‐supplemented counterparts received the day before.…”

Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer's disease

“…The chloroform layer was removed and 20 μL of the solution was taken and evaporated under a stream of nitrogen for GC–MS analysis according to previously published procedures (Kemper et al . ) and quantified directly by comparing the peak area ratio of the pseudo‐molecular ion of the labeled internal standard to that of the native compound.…”

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…An inherent advantage of the former is that 2 moles of physiological d -βOHB are produced per mole of KE, following esterase hydrolysis in the intestine or liver. Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-βOHB, at doses up to 714 mg/kg, yielding circulating d -βOHB concentrations up to 6 mM (Clarke et al, 2012a; Cox et al, 2016; Kemper et al, 2015; Shivva et al, 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al, 2010; Kemper et al, 2015; Veech, 2013).…”

“…Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-βOHB, at doses up to 714 mg/kg, yielding circulating d -βOHB concentrations up to 6 mM (Clarke et al, 2012a; Cox et al, 2016; Kemper et al, 2015; Shivva et al, 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al, 2010; Kemper et al, 2015; Veech, 2013). Recent findings indicate that during exercise in trained athletes, R-3-hydroxybutyl R-βOHB ingestion decreased skeletal muscle glycolysis and plasma lactate concentrations, increased intramuscular triacylglycerol oxidation, and preserved muscle glycogen content, even when co-ingested carbohydrate stimulated insulin secretion (Cox et al, 2016).…”