Oral administration of a Ketone Ester regulates blood cholesterol in rats and humans

Abstract

Control of cholesterol in Type 2 Diabetics and Pre‐diabetics has been problematic as statins increase blood glucose. We propose that a unique β‐hydroxybutyrate (βHB) Ester can provide non‐lipogenic calories and decrease cholesterol synthesis without increasing glucose. The ketone bodies, βHB and Acetoacetate, can be metabolized by most tissues, but not liver, limiting cholesterol precursors. In humans, a single meal containing this ketone ester (KE) dose dependently decreased plasma mevalonate, a marker for cholesterol synthesis, without directly inhibiting HMG‐CoA Reductase. After two days of KE, rats had 31% lower plasma cholesterol and 26% lower mevalonate than controls. In a 30 day study, KE fed rats had lower plasma total cholesterol (‐40%) and mevalonate (‐27%) than controls. Levels of mevalonate precursors, Acetoacetyl‐CoA and HMG‐CoA were lower by 33% and 54% respectively, but Acetyl‐CoA was unaffected. Low liver cholesterol increases absorption of cholesterol through the Low Density Lipoprotein receptor (LDL‐R), KE feeding increased LDL‐R levels in whole cell (+24%) and membrane preparations (+67%). KE fed animals had increased protein levels of SREBP‐2, a key transcriptional activator of LDL‐R, both full length and transcriptionally active forms increased, by 91% and 140%. A 5 day study of KE effect on cholesterol in human Type 2 Diabetics showed not only lower total cholesterol (‐10%) but also lower fasting glucose (‐17%) and Triglycerides (‐18%). We report preliminary findings that KE decreases cholesterol and its synthetic precursors while decreasing fasting blood glucose and triglycerides.