Inhibition of serine palmitoyl transferase I reduces cardiac ceramide levels and increases glycolysis rates following diet-induced insulin resistance.
OBJECTIVE
Diet-induced obesity (DIO) leads to an accumulation of intra-myocardial lipid metabolites implicated in causing cardiac insulin resistance and contractile dysfunction. One such metabolite is ceramide, and our aim was to determine the effects of inhibiting de novo ceramide synthesis on cardiac function and insulin stimulated glucose utilization in mice subjected to DIO.


METHODS
C57BL/6 mice were fed a low fat diet or subjected to DIO for 12 weeks, and then treated for 4 weeks with either vehicle control or the serine palmitoyl transferase I (SPT I) inhibitor, myriocin. In vivo cardiac function was assessed via ultrasound echocardiography, while glucose metabolism was assessed in isolated working hearts.


RESULTS
DIO was not associated with an accumulation of intra-myocardial ceramide, but rather, an accumulation of intra-myocardial DAG (2.63±0.41 vs. 4.80±0.97 nmol/g dry weight). Nonetheless, treatment of DIO mice with myriocin decreased intra-myocardial ceramide levels (50.3±7.7 vs. 26.9±2.7 nmol/g dry weight) and prevented the DIO-associated increase in intra-myocardial DAG levels. Interestingly, although DIO impaired myocardial glycolysis rates (7789±1267 vs. 2671±326 nmol/min/g dry weight), hearts from myriocin treated DIO mice exhibited an increase in glycolysis rates.


CONCLUSIONS
Our data reveal that although intra-myocardial ceramide does not accumulate following DIO, inhibition of de novo ceramide synthesis nonetheless reduces intra-myocardial ceramide levels and prevents the accumulation of intra-myocardial DAG. These effects improved the DIO-associated impairment of cardiac glycolysis rates, suggesting that SPT I inhibition increases cardiac glucose utilization.
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
John R
JR
Ussher
Clifford D L
CD
Folmes
Wendy
W
Keung
Natasha
N
Fillmore
Jagdip S
JS
Jaswal
Virgilio J
VJ
Cadete
Donna L
DL
Beker
Victoria H
VH
Lam
Liyan
L
Zhang
Gary D
GD
Lopaschuk
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D004452:Echocardiography; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D006321:Heart / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007328:Insulin; D051102:Serine C-Palmitoyltransferase; C001996:thermozymocidin