Combined therapy with PPARalpha agonist and L-carnitine rescues lipotoxic cardiomyopathy due to systemic carnitine deficiency.
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 PPARalpha by fenofibrate, a PPARalpha 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 4 weeks 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 8 weeks 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 beta2 in JVS mice. Furthermore, CA + FE prevented the progressive left ventricular dysfunction and dramatically improved the survival rate in JVS mice (survival rate at 400 days after birth: 89 vs. 0%, P < 0.0001).


CONCLUSIONS
PPARalpha 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.
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Japan.
Toru
T
Asai
Kenji
K
Okumura
Ryotaro
R
Takahashi
Hideo
H
Matsui
Yasushi
Y
Numaguchi
Hisashi
H
Murakami
Ryuichiro
R
Murakami
Toyoaki
T
Murohara
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D002331:Carnitine / Q000172:deficiency* / Q000627:therapeutic use; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism; D004359:Drug Therapy, Combination; D004452:Echocardiography; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D011345:Fenofibrate / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011897:Random Allocation; D016896:Treatment Outcome; D014280:Triglycerides / Q000378:metabolism
C011439:1,2-diacylglycerol; D004075:Diglycerides; D005227:Fatty Acids; D047493:PPAR alpha; D047492:Peroxisome Proliferator-Activated Receptors; D014280:Triglycerides; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D002331:Carnitine; D011345:Fenofibrate