Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs.
In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.
Hammond
Linda E
LE
Department of Nutrition, University of North Carolina, North Chapel Hill, Carolina 27599, USA.
Neschen
Susanne
S
Romanelli
Anthony J
AJ
Cline
Gary W
GW
Ilkayeva
Olga R
OR
Shulman
Gerald I
GI
Muoio
Deborah M
DM
Coleman
Rosalind A
RA
D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology; D019422:Dietary Sucrose / Q000494:pharmacology; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D007659:Ketones / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
D004041:Dietary Fats; D019422:Dietary Sucrose; D007659:Ketones; D008055:Lipids; D008246:Lysophospholipids; D014280:Triglycerides; C116917:acylcarnitine; D005992:Glycerol-3-Phosphate O-Acyltransferase; C032881:lysophosphatidic acid; D002331:Carnitine; D003065:Coenzyme A