The current treatment of patients with inherited fatty acid oxidation defects (FOD) involves providing most of the dietary fat as medium even-chain triglycerides (mostly trioctanoin) for long-chain disorders or simply dietary fat restriction for medium- and short chain disorders. This treatment does not prevent, in many cases, the progressive deterioration of cardiac, muscular, and/or retinal function. An initial clinical trial has shown that replacing trioctanoin in the diet by triheptanoin, a medium odd-chain triglyceride, leads to a rapid improvement of the patients' clinical condition and quality of life. We hypothesize that heptanoate, and the C5-ketone bodies derived from its initial hepatic metabolism, exert their beneficial effects by (i) providing propionyI-CoA, an anaplerotic substrate for the citric acid cycle (CAC), and (ii) compensating for partial CAC blockade when the flux through one or more CAC enzymes is restricted. We also hypothesize that odd-chain compounds such as tripentanoin or esters of C5-ketone bodies could be useful in the treatment of medium-chain FOD. Lastly, we hypothesize that a trimer of the C5-ketone body beta-hydroxypentanoate could be used as a slow enteral release form of beta-hydroxypentanoate. We propose a research program to be conducted in mice deficient in very long-chain acyI-CoA dehydrogenase (VLCAD, Aims 1 -4) and in mitochondrial trifunctional protein (MTP, Aim 5).
Our specific aims are: To characterize the metabolism and metabolic effects of the odd-chain compounds in vivo and in perfused organs (heart, muscle and liver). This will be achieved using compounds labeled with 13C in their propionyl or acetyl moiety, to evaluate anaplerosis and oxidation, respectively, by mass isotopomer analysis. 2. To test whether the odd-chain compounds (i) improve the survival of knock-out mice stressed by fasting or/and cold exposure, and (ii) improve energy metabolism and mechanical performance of the heart and muscle under stress-induced conditions (high workload or adrenergic stimulation). 3. To test new avenues for the acute treatment of FOD decompensation, i.e., parenteral preparations of odd-chain anaplerotic substrates (triheptanoin, tripentanoin, glycerol beta-ketopentanoate). To test the practicality of the cyclical trimer of beta-hydroxypentanoate (triolide) as a slow enteric release form of the propionyl-CoA precursor, suitable for nocturnal coverage of patients. To improve the survival of newborn MTP -/- mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069752-02
Application #
7069174
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
May, Michael K
Project Start
2005-06-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$399,146
Indirect Cost
Name
Case Western Reserve University
Department
Nutrition
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Roe, Charles R; Brunengraber, Henri (2015) Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years Experience. Mol Genet Metab 116:260-8
Li, Wei; Bian, Fang; Chaudhuri, Priyanjana et al. (2011) Delineation of substrate selection and anaplerosis in tricarboxylic acid cycle of the heart by 13C NMR spectroscopy and mass spectrometry. NMR Biomed 24:176-87
Gelinas, Roselle; Thompson-Legault, Julie; Bouchard, Bertrand et al. (2011) Prolonged QT interval and lipid alterations beyond ýý-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts. Am J Physiol Heart Circ Physiol 301:H813-23
Gu, Lei; Zhang, Guo-Fang; Kombu, Rajan S et al. (2010) Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile. Am J Physiol Endocrinol Metab 298:E362-71
Kasumov, Takhar; Sharma, Naveen; Huang, Hazel et al. (2009) Dipropionylcysteine ethyl ester compensates for loss of citric acid cycle intermediates during post ischemia reperfusion in the pig heart. Cardiovasc Drugs Ther 23:459-69
Deng, Shuang; Zhang, Guo-Fang; Kasumov, Takhar et al. (2009) Interrelations between C4 ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver. J Biol Chem 284:27799-807
Gelinas, Roselle; Labarthe, Francois; Bouchard, Bertrand et al. (2008) Alterations in carbohydrate metabolism and its regulation in PPARalpha null mouse hearts. Am J Physiol Heart Circ Physiol 294:H1571-80
Roe, C R; Yang, B-Z; Brunengraber, H et al. (2008) Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy. Neurology 71:260-4
Wang, Xiao; Stanley, William C; Darrow, Cory J et al. (2007) Assay of the activity of malonyl-coenzyme A decarboxylase by gas chromatography-mass spectrometry. Anal Biochem 363:169-74
Kasumov, Takhar; Cendrowski, Andrea V; David, France et al. (2007) Mass isotopomer study of anaplerosis from propionate in the perfused rat heart. Arch Biochem Biophys 463:110-7

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