The Expression Pattern of the Acetoacetyl-CoA Synthetase and its Kinetic Parameters Facilitate the Use of Ketone Bodies in Liver during Feeding

Abstract

Acetoacetyl-CoA synthetase (AACS) is a cytoplasmic enzyme that activates the ketone body acetoacetate for lipogenesis. Aacs is expressed in liver, thus this tissue produces and consumes ketone bodies. To understand this apparent paradox we studied the expression of Aacs in liver during the transition from fasting to feeding, and characterized the kinetic parameters of the human enzyme. We show that Aacs liver expression is down-regulated by fasting and only up-regulated after 5 h of refeeding, while the levels of circulating ketone bodies returned to basal levels within 20 min of food availability. Since the human enzyme has a high affinity for the ketone body acetoacetate (KM = 37.6 μM), these results indicates that AACS utilizes ketones during periods of feeding. Human AACS was also characterized as an acetylated enzyme in vivo, where lysine 633 (from a P4XGK domain) plays a critical role in the catalytic activity but not in the acetylation state of the protein.