Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency.
OBJECTIVE
1,2-Diacylglycerol (DAG), a lipid second messenger that activates protein kinase C (PKC), is increased with a distinct fatty acid composition in the heart of the juvenile visceral steatosis (JVS) mouse, which develops pathological cardiac hypertrophy with lipid accumulation induced by the perturbation of fatty acid beta-oxidation due to systemic carnitine deficiency. Fish oil (FO) may exert its beneficial effects on the cardiomyopathy in JVS mice by modifying the molecular species composition of myocardial DAG. To test this hypothesis, we investigated the effects of dietary FO on the hypertrophied hearts in JVS mice.


METHODS
Both control and JVS mice were fed a FO diet (containing 10% FO) or a standard diet from 4 weeks of age.


RESULTS
At 8 weeks of age, the ventricular-to-body weight ratio in JVS mice was 2.7-fold higher than that in controls (9.9 +/- 0.1 vs. 3.7 +/- 0.1 mg/g, P < 0.01) and was reduced by dietary FO (7.7 +/- 0.1 mg/g, P < 0.01 vs. JVS mice). In JVS mice, myocardial DAG levels were elevated by 2.3-fold with a distinct fatty acid composition with increases in C18:1n-7,9 and C18:2n-6 fatty acids compared with controls; dietary FO had no effects on the total DAG levels but significantly altered the fatty acid composition of DAG with reduction of both fatty acid species. Immunoblot analysis showed that dietary FO prevented the membrane translocation of cardiac PKCs alpha, beta2, and epsilon in JVS mice. Dietary FO did not affect the plasma and myocardial total carnitine levels in JVS mice. Furthermore, dietary FO significantly improved the progressive left ventricular dysfunction and survival rate in JVS mice.


CONCLUSIONS
Dietary FO may attenuate cardiac hypertrophy with improvements in cardiac function and survival in JVS mice via modification of the molecular species composition of myocardial DAG and the consequent inhibition of PKC redistribution. These results suggest the implication of the molecular species composition of DAG in the pathogenesis of lipotoxic cardiomyopathy due to perturbations of fatty acid beta-oxidation.
Takahashi
Ryotaro
R
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Japan.
Okumura
Kenji
K
Asai
Toru
T
Hirai
Toshihisa
T
Murakami
Hisashi
H
Murakami
Ryuichiro
R
Numaguchi
Yasushi
Y
Matsui
Hideo
H
Ito
Masafumi
M
Murohara
Toyoaki
T
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002312:Cardiomyopathy, Hypertrophic / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D002331:Carnitine / Q000032:analysis / Q000097:blood / Q000172:deficiency*; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage*; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism; D004452:Echocardiography; D005227:Fatty Acids / Q000032:analysis; D005234:Fatty Liver; D005395:Fish Oils / Q000008:administration & dosage*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D023421:Models, Animal; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism
C011439:1,2-diacylglycerol; D001786:Blood Glucose; D004042:Dietary Fats, Unsaturated; D004075:Diglycerides; D005227:Fatty Acids; D005395:Fish Oils; D008563:Membrane Lipids; D011493:Protein Kinase C; D002331:Carnitine