Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile

Abstract

The anaplerotic odd-medium-chain triglyceride triheptanoin is used in clinical trials for the chronic dietary treatment of patients with long-chain fatty acid oxidation disorders. We previously showed (Kinman RP, Kasumov T, Jobbins KA, Thomas KR, Adams JE, Brunengraber LN, Kutz G, Brewer WU, Roe CR, Brunengraber H. Am J Physiol Endocrinol Metab 291: E860-E866, 2006) that the intravenous infusion of triheptanoin increases lipolysis traced by the turnover of glycerol. In this study, we tested whether lipolysis induced by triheptanoin infusion is accompanied by the potentially harmful release of long-chain fatty acids. Rats were infused with heptanoate +/- glycerol or triheptanoin. Intravenous infusion of triheptanoin at 40% of caloric requirement markedly increased glycerol endogenous R(a) but not oleate endogenous R(a). Thus, the activation of lipolysis was balanced by fatty acid reesterification in the same cells. The liver acyl-CoA profile showed the accumulation of intermediates of heptanoate beta-oxidation and C(5)-ketogenesis and a decrease in free CoA but no evidence of metabolic perturbation of liver metabolism such as propionyl overload. Our data suggest that triheptanoin, administered either intravenously or intraduodenally, could be used for intensive care and nutritional support of metabolically decompensated long-chain fatty acid oxidation disorders.

Figures

Fig. 1.

Interrelations between C4-ketogenesis from even-chain fatty acids, C5-ketogenesis from odd-chain fatty acids, and anaplerosis in the liver. The numbers in italics refer to the following enzymes: 3-ketoacyl-CoA thiolase (1), hydroxymethylglutaryl (HMG)-CoA synthase (2), HMG-CoA lyase (3), and β-hydroxybutyrate (BHB) dehydrogenase (4). This figure also shows the link between propionyl-CoA and the citric acid cycle (CAC) via anaplerosis (modified from Ref. 3). BHP, β-hydroxypentanoate; AcAc, acetoacetate; BKP, β-ketopentanoate; HEG, 3-hydroxy-3-ethylglutaryl.

Fig. 2.

Profile of heptanoate concentrations in rat plasma. In this and subsequent figures, data are presented as means ± SE (n = 6). iv, Intravenous; TH, triheptanoin; id, intraduodenal.

Fig. 3.

Profile of total C5-ketone body concentrations in plasma.

Fig. 4.

Profile of total C4-ketone body concentrations in plasma.

Fig. 5.

Profile of glycerol concentrations in plasma.

Fig. 6.

Profile of glucose concentrations in plasma.

Fig. 7.

Profile of oleate M18 enrichment (A) and concentration (B) in plasma. MPE, molar %enrichment.

Fig. 8.

Comparison between the glucose endogenous rates of appearance (Ra) (open bars), the rate of liver glycogen synthesis over control (cross-hatched bars), and the potential glucose productions from 1) endogenous glycerol Ra (vertically hatched bars), 2) exogenous glycerol (diagonally hatched bars), and 3) exogenous propionyl equivalents derived from heptanoate or triheptanoin (black bars). All rates are expressed in μmol glucose equivalents·min−1·kg−1. SE for endogenous glycerol and glucose Ra are shown in Table 3.