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Carnitine Palmitoyltransferase 2 (CPT2) Inhibition in Rats And Dogs Resembles Inborn Human CPT2 Deficiency
Author(s) -
DE VERA MUDRY MARIA CRISTINA,
FESTAG MATTHIAS,
HOFLACK JEANCHRISTOPHE,
CRAMERI FLAVIO
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.612.3
Subject(s) - endocrinology , medicine , carnitine , beta oxidation , mitochondrial toxicity , mitochondrial myopathy , myoglobinuria , kidney , hyperammonemia , toxicity , myopathy , rhabdomyolysis , biology , biochemistry , metabolism , mitochondrial dna , gene
Carnitine palmitoyltransferases (CPT1 and 2) regulate the rate of fatty acid oxidation through intake of long‐chain fatty acids (LCFA) into mitochondria. Inhibition of CPT can reduce gluconeogenesis by decreasing LCFA and acetyl‐CoA in the liver. CPT inhibitors are therefore proposed as a potential therapeutic approach to reduce hyperglycemia in diabetes. Inborn human CPT deficiency is associated with multiorgan toxicity such as muscle weakness, rhabdomyolyis, myoglobinuria, tissue accumulation of lipids and acylcarnitines, and associated degeneration and mitochondrial damage. Methods To assess the safety of therapeutic CPT inhibition, a selective inhibitor of CPT2 was given daily by oral gavage to Wistar rats for 14 days, or to Beagle dogs in a single ascending‐dose phase followed by a 7‐day fixed‐dose phase. Results Clinical signs of CPT2 inhibition consisted of hypoactivity, salivation, emesis (dogs), and body weight loss. At high doses, rats were moribund or died after overnight fasting. Laboratory parameters, gross and histopathology, and transcriptomic profiles (rat liver) indicated liver, kidney, and muscle toxicity. Pale liver, kidney, and heart correlated with increased lipid deposits. Hepatocellular apoptosis, skeletal muscle atrophy and myodegeneration were also present. Electron microscopy of rat liver and muscle revealed mitochondrial damage. Conclusion On‐target toxicity of a CPT2 inhibitor in the liver, kidney, muscle, and heart in rats and dogs recapitulates and serves as a model of inherited human CPT2 deficiency.