Mice deficient in mitochondrial glycerol-3-phosphate acyltransferase-1 have diminished myocardial triacylglycerol accumulation during lipogenic diet and altered phospholipid fatty acid composition.
Glycerol-3-phosphate acyltransferase-1 (GPAT1), which is located on the outer mitochondrial membrane comprises up to 30% of total GPAT activity in the heart. It is one of at least four mammalian GPAT isoforms known to catalyze the initial, committed, and rate-limiting step of glycerolipid synthesis. Because excess triacylglycerol (TAG) accumulates in cardiomyocytes in obesity and type 2 diabetes, we determined whether lack of GPAT1 would alter the synthesis of heart TAG and phospholipids after a 2-week high-sucrose diet or a 3-month high-fat diet. Even in the absence of hypertriglyceridemia, TAG increased 2-fold with both diets in hearts from wildtype mice. In contrast, hearts from Gpat1(-/-) mice contained 20-80% less TAG than the wildtype controls. In addition, hearts from Gpat1(-/-) mice fed the high-sucrose diet incorporate 60% less [(14)C]palmitate into heart TAG as compared to wildtype mice. Because GPAT1 prefers 16:0-CoA to other long-chain acyl-CoA substrates, we determined the fatty acid composition of heart phospholipids. Compared to wildtype littermate controls, hearts from Gpat1(-/-)(-/-) mice contained a lower amount of 16:0 in phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine/phosphatidylinositol and significantly more C20:4n6. Phosphatidylcholine and phosphatidylethanolamine from Gpat1(-/-)(-/-) hearts also contained higher amounts of 18:0 and 18:1. Although at least three other GPAT isoforms are expressed in the heart, our data suggest that GPAT1 contributes significantly to cardiomyocyte TAG synthesis during lipogenic or high-fat diets and influences the incorporation of 20:4n6 into heart phospholipids.
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA. tal_lewin@unc.edu
Tal M
TM
Lewin
Hendrik
H
de Jong
Nicole J M
NJ
Schwerbrock
Linda E
LE
Hammond
Steven M
SM
Watkins
Terry P
TP
Combs
Rosalind A
RA
Coleman
D000818:Animals; D001483:Base Sequence; D002384:Catalysis; D017931:DNA Primers; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism*; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D006321:Heart; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D009206:Myocardium / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D013395:Sucrose / Q000008:administration & dosage; D014280:Triglycerides / Q000378:metabolism*
D017931:DNA Primers; D005227:Fatty Acids; D010743:Phospholipids; D014280:Triglycerides; D013395:Sucrose; D005992:Glycerol-3-Phosphate O-Acyltransferase