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Potential of Anaplerotic Triheptanoin for the Treatment of Long-chain Fatty Acid Oxidation Disorders

Gu, Lei
http://rave.ohiolink.edu/etdc/view?acc_num=case1263926817

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Long-chain fatty acid oxidation disorders are the genetic and metabolic diseases in which the body is unable to break down long-chain fatty acids to make energy. The anaplerotic medium-odd-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 that the intravenous infusion of triheptanoin increases lipolysis traced by the turnover of glycerol (Kinman RP et al Am. J. Physiol. 291: E860-E866, 2006). In the present study, we tested whether lipolysis induced by triheptanoin infusion is accompanied by the potentially harmful release of long-chain fatty acids. Overnight fasted rats were infused with heptanoate ± glycerol, or triheptanoin ± (glucose + insulin), through parenteral or enteral route. The liver metabolism of heptanoate β-oxidation has two main fates: (i) anaplerotic gluconeogenesis from the propionyl moiety, and (ii) formation of C5-ketone bodies. Intravenous infusion of heptanoate alone or with glycerol did not affect endogenous glycerol Ra and oleate Ra, but increased endogenous glucose Ra from gluconeogenic precursors. Intravenous infusion of triheptanoin at 40% of caloric requirements markedly increased endogenous glycerol turnover but not endogenous oleate turnover. Thus, the activation of lipolysis was balanced by fatty acid re-esterification in the same cells. The provision of glycerol-3-phosphate for fatty acid re-esterification is most likely derived from hyperglycemia and the increased glucose turnover during intravenous infusion of triheptanoin. Intravenous infusion of triheptanoin under hyperglycemia and hyperinsulinemia conditions inhibited heptanoate utilization and C4-, C5-ketogenesis, as well as halved endogenous glycerol turnover and oleate turnover. Intraduodenal infusion of triheptanoin did not activate lipolysis. The liver acyl-CoA profile showed the accumulation of intermediates of heptanoate β-oxidation and C5-ketogenesis, and a decrease in free CoA, but no evidence of metabolic perturbations of liver metabolism. Our data suggest that triheptanoin, administered either intravenously or intraduodenally, could be used for intensive care and nutritional support of metabolic decompensated patients including long-chain fatty acid oxidation disorders.
Henri Brunengraber, PhD, MD (Advisor)
Edith Lerner, PhD (Committee Chair)
Janos Kerner, PhD (Committee Member)
Colleen Croniger, PhD (Committee Member)
Michelle Puchowicz, PhD (Committee Member)
198 p.
FATTY ACID; TRIHEPTANOIN; FATTY; LIPOLYSIS; Heptanoate; ACID; Glycerol

Recommended Citations

Citations

  • Gu, L. (2010). Potential of Anaplerotic Triheptanoin for the Treatment of Long-chain Fatty Acid Oxidation Disorders [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1263926817

    APA Style (7th edition)

  • Gu, Lei. Potential of Anaplerotic Triheptanoin for the Treatment of Long-chain Fatty Acid Oxidation Disorders. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1263926817.

    MLA Style (8th edition)

  • Gu, Lei. "Potential of Anaplerotic Triheptanoin for the Treatment of Long-chain Fatty Acid Oxidation Disorders." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1263926817

    Chicago Manual of Style (17th edition)

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© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.