Activity and expression of hepatic mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase during the starved-to-fed transition.

Refeeding starved rats for 2-3 h completely reverses the effects of starvation on hepatic ketogenic capacity [ 11 and decreases blood ketone body concentrations markedly [2]. However, acute depression of ketogenesis on refeeding is not accompanied by any reversal of changes (induced by starvat ion) in carnitine palmitoyltransferase (CPT ) I during the first 6 h o f refeeding [2, 31, indicating that control is exerted at other (intramitochondrial) regulatory site(s) (distal to CPT I ) during the rapid reversal of starvation ketosis. (CPT I is an important locus for the control of ketogenic flux in the livers of normal fed adult rats [4,5].) I have used the ‘top-down’ approach [6] of Metabolic Control Theory 17-01 to establish that, in addition to CPT I, the enzymes o f the 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) pathway (acetoacetyl-CoA thiolase, HMG-CoA synthase and HMG-CoA lyase) can contribute significantly to control of ketogenesis [lo]. My earlier findings [ 11-15] and those of others [ 16, 171 suggest this control may be exerted at the level of mitochondria1 HMG-CoA synthase (EC 4.1.3.5). My research has shown that changes in the rate of ketone body production occur in parallel with changes in the activity of the key enzyme mitochondrial HMG-CoA synthase [ 1 I ] . These changes result from glucagon-induced changes in succinylation (and inactivation) of the synthase and from changes in the absolute amounts of the enzyme protein [ 1 215 I . The pool of succinylated (inactivated) enzyme allows for rapid fine control of HMG-CoA synthase (and hence ketogenesis) as metabolic requirements change (e.g. during the fetal-neonatal transition) [ 131. This is an insulinindependent control. A change in the absolute amounts of enzyme appears to be a more acute long-term response to changes in nutrition (starvation or fat feeding) and hormone levels (diabetes, starvation or fat feeding) I 13-1 51. Elevated levels o f glucagon stimulate ketogenesis. High levels of insulin depress it [18-2OJ. Starvation results in an increased glucagon/insulin concentration ratio and refeeding reverses this (see 1.31). The aim of this present paper is to establish whether the rapid depression of ketogenesis o n refeeding can be explained by rapid resuccinylation and inactivation of HMG-CoA synthase (induced by the decreasing glucagon Icvels).