Comparative effects of (?)-hydroxycitrate and (+)-allo-hydroxycitrate on acetyl CoA carboxylase and fatty acid and cholesterol synthesis in vivo

(−)-Hydroxycitrate and (+)-allo-hydroxycitrate were investigated for their effects on lipid synthesis in vivo under conditions of either high carbohydrate feeding or 24 hr fasting. Changes in rates of lipid synthesis resulting from the oral administration of these compounds were monitored with the use of radiolabeled H₂O, alanine, and acetate. In the fed rat, (−)-hydroxycitrate significantly reduced the incorporation of H₂O and alanine into fatty acids and cholesterol. An increased incorporation of labeled H₂O into fatty acids but no change in cholesterol synthesis in the fasted rat suggested that (−)-hydroxycitrate may be an activator of acetyl CoA carboxylase. With (−)-hydroxycitrate administration, acetate incorporation into fatty acids and cholesterol was subject to pool dilution effects under fed or fasted states. (+)-allo-Hydroxycitrate was ineffective in modulating the rates of fatty acid synthesis under either nutritional condition. Both (−)-hydroxycitrate and (+)-allo-hydroxycitrate were shown to be in vitro activators of acetyl CoA carboxylase, the former being a much stronger activator than the latter. Thus, stereospecificity of the hydroxycitrate isomers was demonstrated in both the inhibition of lipid synthesis (previously shown to occur at adenosine triphosphate citrate lyase) and the stimulation of fatty acid synthesis (possibly occurring at acetyl CoA carboxylase).