J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M300190-JLR200 on August 16, 2003

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Journal of Lipid Research, Vol. 44, 2089-2099, November 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue

Robert Zimmermann1,*, Guenter Haemmerle1,*, Elke M. Wagner*, Juliane G. Strauss*, Dagmar Kratky{dagger} and Rudolf Zechner2,*

* Institute of Molecular Biology, Biochemistry, and Microbiology, University of Graz, Graz, Austria
{dagger} Institute of Medical Biochemistry and Medical Molecular Biology, University of Graz, Graz, Austria

2 To whom correspondence should be addressed. e-mail: rudolf.zechner{at}kfunigraz.ac.at

It has been observed previously that hormone-sensitive lipase-deficient (HSL-ko) mice have reduced white adipose tissue (WAT) stores compared to control mice. These findings contradict the expectation that the decreased lipolytic activity in WAT of HSL-ko mice would cause accumulation of triglycerides (TGs) in that tissue. Here we demonstrate that the cellular TG synthesis in HSL-deficient WAT is markedly reduced due to downregulation of the enzymatic activities of glycerophosphate acyltransferase, dihydroxyacetonphosphate acyltransferase, lysophosphatidate acyltransferase, and diacylglycerol acyltransferase. Fatty acid de novo synthesis is also decreased due to reduced cellular glucose uptake, reduced glucose incorporation into adipose tissue lipids, and reduced activities of acetyl:CoA carboxylase and fatty acid synthase. Finally, the activities of phosphoenolpyruvate carboxykinase (PEPCK), acyl:CoA synthetase (ACS), and glucose 6-phosphate dehydrogenase, the enzymes that provide glycerol-3-phosphate, acyl-CoA, and NADPH for TG synthesis, respectively, are decreased in HSL-ko mice. The reduced expression of the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) target genes PEPCK, ACS, and aP2, as well as reduced mRNA levels of PPAR{gamma} itself, suggest the involvement of this transcription factor in the downregulation of lipogenesis.

Taken together, these results establish that in the absence of HSL, the reduced NEFA production is counteracted by a drastic reduction of NEFA reesterification that provides sufficient quantities of NEFA for release into the circulation. These metabolic adaptations result in decreased fat mass in HSL-ko mice.

Abbreviations: ACC, acetyl-CoA carboxylase; ACS, acyl-CoA-synthetase; aP2, adipocyte fatty acid binding protein; DGAT, diacylglycerol acyltransferase; FAS, fatty acid synthase; G6PDH, glucose-6-phosphate dehydrogenase; GNPAT, glycerophosphate acyltransferase; GPAM, mitochondrial GPAT; GPAT, glycerol-3-phosphate acyltransferase; HSL, hormone-sensitive lipase; LPAAT, lysophosphatidate acyltransferase; PEPCK, phosphoenolpyruvate carboxykinase; PL, phospholipid; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element binding protein; TG, triglyceride; WAT, white adipose tissue

Supplementary key words triglyceride synthesis • fatty acid synthesis • peroxisome proliferator-activated receptor {gamma}


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