The lipogenic enzyme acetoacetyl-CoA synthetase and ketone body utilization for denovo lipid synthesis, a review

Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and ATP citrate lyase. This review shows that AACS is a highly regulated, cytosolic and lipogenic enzyme and that many tissues can readily use KBs for denovo lipid synthesis. AACS has a low, micromolar Km for acetoacetate (AcAc) and supply of AcAc should not limit its activity in the fed state. In many tissues AACS appears to be regulated in conjunction with the need for cholesterol, but in adipose tissue it seems tied to fatty acid synthesis. KBs are readily utilized as substrates for lipid synthesis in lipogenic tissues including liver, adipose tissue, lactating mammary gland, skin, intestinal mucosa, adrenals and developing brain. In numerous studied cases, KBs served several-fold better than glucose as substrates for lipid synthesis and when present, KBs suppressed the utilization of glucose for lipid synthesis. Here it is hypothesized that a physiological role for the utilization of KBs for lipid synthesis is a metabolic process of lipid interconversion. Fatty acids are converted to KBs in liver and then the KBs are utilized to synthesize cholesterol and other long-chainfatty acids in liver and non-hepatic tissues. The conversion of fatty acids to cholesterol via the KBs may be a particularly important example of lipid interconversion. Utilizing KBs for lipid synthesis is glucose sparing and probably is important with low carbohydrate diets. Metabolic situations and tissues where lipid interconversion may be important are discussed.