Copyright © 2006, European Society of Cardiology
Combined therapy with PPAR
agonist and L-carnitine rescues lipotoxic cardiomyopathy due to systemic carnitine deficiency
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
* Corresponding author. Tel.: +81 52 744 2168; fax: +81 52 744 2177. Email address: kenji{at}med.nagoya-u.ac.jp
Objective Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and are key regulators of fatty acid oxidation (FAO) in the heart. Systemic carnitine deficiency (SCD) causes disorders of FAO and induces hypertrophic cardiomyopathy with lipid accumulation. We hypothesized that activation of PPAR
by fenofibrate, a PPAR agonist, in addition to conventional L-carnitine supplementation may exert beneficial effects on the lipotoxic cardiomyopathy in juvenile visceral steatosis (JVS) mouse, a murine model of SCD.
Methods Both wild-type (WT) and JVS mice were fed a normal chow, 0.2% fenofibrate containing chow (FE), a 0.1% L-carnitine containing chow (CA) or a 0.1% L-carnitine+0.2% fenofibrate containing chow (CA+FE) from 4weeks of age. Four to 8 animals per group were used for each experiment and 9 to 11 animals per group were used for survival analysis.
Results At 8weeks of age, JVS mice exhibited marked ventricular hypertrophy, which was more attenuated by CA+FE than by CA or FE alone. CA+FE markedly reduced the high plasma and myocardial triglyceride levels and increased the low myocardial ATP content to control levels in JVS mice. In JVS mice, myocardial 1,2-diacylglycerol (DAG) was significantly increased and showed a distinct fatty acid composition with elevation of 18:1(n – 7,9) and 18:2(n – 6) fatty acids compared with that in WT mice. CA+FE significantly altered the fatty acid composition of DAG and inhibited the membrane translocation of cardiac protein kinase C β2 in JVS mice. Furthermore, CA+FE prevented the progressive left ventricular dysfunction and dramatically improved the survival rate in JVS mice (survival rate at 400days after birth: 89 vs. 0%, P<0.0001).
Conclusions PPAR activation, in addition to L-carnitine supplementation, may rescue the detrimental lipotoxic cardiomyopathy in SCD by improving cardiac energy and lipid metabolism as well as systemic lipid metabolism.
KEYWORDS Cardiomyopathy; Hypertrophy; Lipid metabolism; Lipid signaling; Energy metabolism
Time for primary review 34 days
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