New, Karen Jayne; (2001) Control of hepatic fatty acid oxidation in suckling rats. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this thesis, I use metabolic control analysis to investigate quantitatively, the control of neonatal hepatic fatty acid oxidation and ketogenesis. Specifically, I model, report and discuss the control of hepatic fatty acid oxidation, Krebs cycle and ketogenic fluxes by mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), in hepatocytes or mitochondria isolated from suckling rats, under physiological and (patho)physiological conditions, mimicking healthy and diseased states. My work has: (a) provided the first quantitative assessment of the control exerted by CPT I over carbon fluxes from palmitate, octanoate and palmitate: octanoate mixtures, in hepatocytes isolated from suckling rats; (b) provided a quantitative assessment of the control exerted by CPT I over ketogenesis and total carbon flux from palmitate, in a re-defined system, in mitochondria isolated from suckling or adult rats (Krauss, et al., 1996); (c) shown that the numerical value of the flux control coefficient for CPT I over ketogenesis changes with developmental stage and is lower in suckling rats than in adult rats in both hepatocyte and mitochondrial systems; (d) demonstrated that the numerical value of the flux control coefficient for CPT I over ketogenesis changes in response to different substrates; (e) indicated that whilst in adult rats, CPT I exerts a high level of control over ketogenesis in neonatal rats, CPT I is not 'rate-limiting' over ketogenesis, under physiological conditions; (f) provided the first quantitative assessment of the control exerted by CPT I over carbon fluxes from palmitate in an in vitro model of neonatal sepsis; (g) demonstrated that the potential of CPT I to control ketogenesis increases under certain (patho)physiological conditions; (h) provided an investigation into hepatocyte respiration under (patho)physiological conditions and has shown that in this in vitro model of neonatal sepsis, oxygen consumption is increased.

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