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Liver‐directed overexpression of mitochondrial glycerol‐3‐phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation
Author(s) -
Lindén Daniel,
WilliamOlsson Lena,
Ahnmark Andrea,
Ekroos Kim,
Hallberg Carina,
Sjögren Helena P.,
Becker Bruno,
Svensson Lennart,
Clapham John C.,
Oscarsson Jan,
Schreyer Sandra
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4568com
Subject(s) - steatosis , fatty liver , acyltransferase , biochemistry , diacylglycerol kinase , beta oxidation , medicine , endocrinology , fatty acid , chemistry , biology , phospholipid , enzyme , protein kinase c , disease , membrane
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, D., William‐Olsson, L., Ahnmark, A., Ekroos, K., Hallberg, C., Sjögren, H. P., Becker, B., Svensson, L., Clapham, J. C., Oscarsson, J., Schreyer, S. Liver‐directed overexpression of mitochondrial glycerol‐3‐phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J. 20, 434–443 (2006)