Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis
Glycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtG...
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doaj-1ab501f64cb840eeb6834a6084b533022021-04-27T04:40:42ZengElsevierJournal of Lipid Research0022-22752004-07-0145712791288Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesisDaniel Lindén0Lena William-Olsson1Magdalena Rhedin2Anna-Karin Asztély3John C. Clapham4Sandra Schreyer5AstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenAstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenAstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenAstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenAstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenAstraZeneca R&D, Mölndal, Sweden; Wallenberg Laboratory for Cardiovascular Research, Göteborg University, SwedenGlycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from β-oxidation and toward glycerolipid synthesis. Adenoviral-mediated overexpression of murine mtGPAT in primary cultures of rat hepatocytes increased mtGPAT activity 2.7-fold with no compensatory effect on microsomal GPAT activity. MtGPAT overexpression resulted in a dramatic 80% reduction in fatty acid oxidation and a significant increase in hepatic diacylglycerol and phospholipid biosynthesis. Following lipid loading of the cells, intracellular triacylglycerol biosynthesis was also induced by mtGPAT overexpression. Changing an invariant aspartic acid residue to a glycine [D235G] in mtGPAT resulted in an inactive enzyme, which helps define the active site required for mammalian mtGPAT function. To determine if obesity increases hepatic mtGPAT activity, two models of rodent obesity were examined and shown to have >2-fold increased enzyme activity.Overall, these results support the concept that increased hepatic mtGPAT activity associated with obesity positively contributes to lipid disorders by reducing oxidative processes and promoting de novo glycerolipid synthesis.http://www.sciencedirect.com/science/article/pii/S0022227520317843glycerol-3-phosphate acyltransferaseobesitytriglyceride |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel Lindén Lena William-Olsson Magdalena Rhedin Anna-Karin Asztély John C. Clapham Sandra Schreyer |
spellingShingle |
Daniel Lindén Lena William-Olsson Magdalena Rhedin Anna-Karin Asztély John C. Clapham Sandra Schreyer Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis Journal of Lipid Research glycerol-3-phosphate acyltransferase obesity triglyceride |
author_facet |
Daniel Lindén Lena William-Olsson Magdalena Rhedin Anna-Karin Asztély John C. Clapham Sandra Schreyer |
author_sort |
Daniel Lindén |
title |
Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
title_short |
Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
title_full |
Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
title_fullStr |
Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
title_full_unstemmed |
Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
title_sort |
overexpression of mitochondrial gpat in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2004-07-01 |
description |
Glycerol-3-phosphate acyltransferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver, where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from β-oxidation and toward glycerolipid synthesis. Adenoviral-mediated overexpression of murine mtGPAT in primary cultures of rat hepatocytes increased mtGPAT activity 2.7-fold with no compensatory effect on microsomal GPAT activity. MtGPAT overexpression resulted in a dramatic 80% reduction in fatty acid oxidation and a significant increase in hepatic diacylglycerol and phospholipid biosynthesis. Following lipid loading of the cells, intracellular triacylglycerol biosynthesis was also induced by mtGPAT overexpression. Changing an invariant aspartic acid residue to a glycine [D235G] in mtGPAT resulted in an inactive enzyme, which helps define the active site required for mammalian mtGPAT function. To determine if obesity increases hepatic mtGPAT activity, two models of rodent obesity were examined and shown to have >2-fold increased enzyme activity.Overall, these results support the concept that increased hepatic mtGPAT activity associated with obesity positively contributes to lipid disorders by reducing oxidative processes and promoting de novo glycerolipid synthesis. |
topic |
glycerol-3-phosphate acyltransferase obesity triglyceride |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520317843 |
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