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Journal of Lipid Research, Vol. 45, 356-365, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Defective uptake of triglyceride-associated fatty acids in adipose tissue causes the SREBP-1c-mediated induction of lipogenesis

Elke M. Wagner^1,*, Dagmar Kratky^1,, Guenter Haemmerle^*, Andelko Hrzenjak, Gert M. Kostner, Ernst Steyrer and Rudolf Zechner^2,*

^* Institute of Molecular Biology, Biochemistry, and Microbiology, University of Graz, Graz, Austria
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}uni-graz.at

Lipoprotein lipase (LPL) is the only known enzyme in the capillary endothelium of peripheral tissues that hydrolizes plasma triglycerides and provides fatty acids (FAs) for their subsequent tissue uptake. Previously, we demonstrated that mice that express LPL exclusively in muscle develop essentially normal fat mass despite the absence of LPL and the deprivation of nutritionally derived FAs in adipose tissue (AT). Using this mouse model, we now investigated the metabolic response to LPL deficiency in AT that enables maintenance of normal AT mass. We show that the rate of FA production was 1.8-fold higher in LPL-deficient AT than in control AT. The levels of mRNA and enzymatic activities of important enzymes involved in FA and triglyceride biosynthesis were induced concomitantly. Increased plasma glucose clearing and ¹⁴C-deoxyglucose uptake into LPL-deficient mouse fat pads indicated that glucose provided the carbon source for lipid synthesis. Leptin expression was decreased in LPL-deficient AT. Finally, the induction of de novo FA synthesis in LPL-deficient AT was associated with increased expression and processing of sterol regulatory element binding protein 1 (SREBP-1), together with an increase in INSIG-1 expression. These results suggest that in the absence of LPL in AT, lipogenesis is activated through increased SREBP-1 expression and processing triggered by decreased availability of nutrition-derived FAs, elevated insulin, and low leptin levels.

Abbreviations: ACC, acetyl-CoA carboxylase; AT, adipose tissue; ATP-CL, ATP-dependent citrate lyase; DGAT, acyl-CoA:diacylglycerol acyltransferase; FA, fatty acid; FAS, fatty acid synthase; G6PDH, glucose-6-phosphate dehydrogenase; HSL, hormone-sensitive lipase; INSIG, insulin-induced gene; LPL, lipoprotein lipase; MCK, mouse creatine kinase; ME, malic enzyme; PDH, pyruvate dehydrogenase; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element binding protein; TG, triglyceride

Supplementary key words fatty acid biosynthesis • lipoprotein lipase • lipogenic enzymes • sterol regulatory element binding protein • insulin-induced gene • leptin • polyunsaturated fatty acid

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