Oral administration of a β-hydroxybutyrate ester regulates blood cholesterol in rats and humans

Authors

• MF Kemper
• S Srivastava
• MT King
• K Clarke
• RL Veech
• RJ Pawlosky

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 for 30 days on a diet containing KE (30% of calories) substituted for carbohydrate, had lower plasma total 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% of calories as KE) had elevated plasma βHB which correlated with decreased mevalonate, a liver cholesterol synthesis biomarker. A preliminary 5 day study of KE effect on cholesterol in human Type 2 Diabetics showed not only lower total non-LDL cholesterol (-13%) but also lower fasting glucose (-17%) and Triglycerides (-18%). We report findings that KE decreases cholesterol and its synthetic precursors and preliminary findings that it may also decrease fasting blood glucose and triglycerides.

Scientific Focus Area: Molecular Biology and Biochemistry

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