Abstract
It is increasingly recognized that synthesis and turnover of cardiac triglyceride (TG) play a pivotal role in the regulation of lipid metabolism and function of the heart. The last step in TG synthesis is catalyzed by diacylglycerol:acyltransferase (DGAT) which esterifies the diacylglycerol with a fatty acid. Mammalian heart has two DGAT isoforms, DGAT1 and DGAT2, yet their roles in cardiac metabolism and function remain poorly defined. Here, we show that inactivation of DGAT1 or DGAT2 in adult mouse heart results in a moderate suppression of TG synthesis and turnover. Partial inhibition of DGAT activity increases cardiac fatty acid oxidation without affecting PPARα signaling, myocardial energetics or contractile function. Moreover, coinhibition of DGAT1/2 in the heart abrogates TG turnover and protects the heart against high fat diet-induced lipid accumulation with no adverse effects on basal or dobutamine-stimulated cardiac function. Thus, the two DGAT isoforms in the heart have partially redundant function, and pharmacological inhibition of one DGAT isoform is well tolerated in adult hearts.
Highlights
The final step in TG synthesis is catalyzed by DGAT 1 and 2, both of which are present in the heart
We observed that deletion of DGAT1 only modestly reduced TG synthesis from exogenous fatty acids which correlated with increased fatty acid oxidation and had no effect on cardiac function up to 1 year of age
We found that DGAT2 compensated for DGAT1 function in inducible DGAT1 knockout (iKO) and that inhibition of both isoforms abrogated TG synthesis but did not alter cardiac response to high fat diet
Summary
The final step in TG synthesis is catalyzed by DGAT 1 and 2, both of which are present in the heart. The DGAT1-null mice had normal levels of TG and diacylglycerol (DAG) in the heart[10] while cardiac specific deletion of DGAT1 was sufficient to increase DAG levels without effecting TG levels[13]. TG turnover rate was shown closely correlated with PPARα activity and cardiac function[5,14,15]. In the present study we determined the role of DGAT 1 and 2 in TG synthesis and turnover in the heart as well as their contributions to cardiac fatty acid metabolism. We observed that deletion of DGAT1 only modestly reduced TG synthesis from exogenous fatty acids which correlated with increased fatty acid oxidation and had no effect on cardiac function up to 1 year of age. We found that DGAT2 compensated for DGAT1 function in iKO and that inhibition of both isoforms abrogated TG synthesis but did not alter cardiac response to high fat diet
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