Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation.
Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step in triacylglycerol (TAG) and phospholipid biosynthesis. GPAT activity has been identified in both ER and mitochondrial subcellular fractions. The ER activity dominates in most tissues except in liver, where the mitochondrial isoform (mtGPAT) can constitute up to 50% of the total activity. To study the in vivo effects of hepatic mtGPAT overexpression, mice were transduced with adenoviruses expressing either murine mtGPAT or a catalytically inactive variant of the enzyme. Overexpressing mtGPAT resulted in massive 12- and 7-fold accumulation of liver TAG and diacylglycerol, respectively but had no effect on phospholipid or cholesterol ester content. Histological analysis showed extensive lipid accumulation in hepatocytes. Furthermore, mtGPAT transduction markedly increased adipocyte differentiation-related protein and stearoyl-CoA desaturase-1 (SCD-1) in the liver. In line with increased SCD-1 expression, 18:1 and 16:1 in the hepatic TAG fraction increased. In addition, mtGPAT overexpression decreased ex vivo fatty acid oxidation, increased liver TAG secretion rate 2-fold, and increased plasma TAG and cholesterol levels. These results support the hypothesis that increased hepatic mtGPAT activity associated with obesity and insulin resistance contributes to increased TAG biosynthesis and inhibition of fatty acid oxidation, responses that would promote hepatic steatosis and dyslipidemia.
Lindén
Daniel
D
Department of Integrative Pharmacology, AstraZeneca R&D, S-431 83 Mölndal, Sweden. daniel.linden@astrazeneca.com
William-Olsson
Lena
L
Ahnmark
Andrea
A
Ekroos
Kim
K
Hallberg
Carina
C
Sjögren
Helena P
HP
Becker
Bruno
B
Svensson
Lennart
L
Clapham
John C
JC
Oscarsson
Jan
J
Schreyer
Sandra
S
D019943:Amino Acid Substitution; D000818:Animals; D002241:Carbohydrates / Q000096:biosynthesis; D004075:Diglycerides / Q000378:metabolism; D004790:Enzyme Induction; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000096:biosynthesis* / Q000235:genetics; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology*; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism*
D002241:Carbohydrates; D004075:Diglycerides; D005227:Fatty Acids; D008055:Lipids; D010743:Phospholipids; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D005992:Glycerol-3-Phosphate O-Acyltransferase