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Journal of Lipid Research, Vol. 47, 2297-2305, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Short-term overexpression of DGAT1 or DGAT2 increases hepatic triglyceride but not VLDL triglyceride or apoB production

John S. Millar^1,*, Scot J. Stone^,, Uwe J. F. Tietge^**, Bryan Tow, Jeffrey T. Billheimer^**, Jinny S. Wong^,, Robert L. Hamilton^,, Robert V. Farese, Jr.^, and Daniel J. Rader^**

^* Department of Pharmacology, University of Pennsylvania, Philadelphia, PA
Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, CA
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA
^** Department of Medicine, University of Pennsylvania, Philadelphia, PA
Department of Anatomy, University of California at San Francisco, San Francisco, CA

Published, JLR Papers in Press, July 30, 2006.

¹ To whom correspondence should be addressed. e-mail: jsmillar{at}mail.med.upenn.edu

Increased triglyceride synthesis resulting from enhanced flux of fatty acids into liver is frequently associated with VLDL overproduction. This has led to the common belief that hepatic triglyceride synthesis can directly modulate VLDL production. We used adenoviral vectors containing either murine acyl-coenzyme A:diacylglycerol transferase 1 (DGAT1) or DGAT2 cDNA to determine the effect of a short-term increase in hepatic triglyceride synthesis on VLDL triglyceride and apolipoprotein B (apoB) production in female wild-type mice. Hepatic DGAT1 and DGAT2 overexpression resulted in 2.0-fold and 2.4-fold increases in the triglyceride content of liver, respectively. However, the increase in hepatic triglyceride content had no effect on the production rate of VLDL triglyceride or apoB in either case. Liver subfractionation showed that DGAT1 and DGAT2 overexpression significantly increased the content of triglyceride within the cytoplasmic lipid fraction, with no change in the triglyceride content of the microsomal membrane or microsomal VLDL. The increased cytoplasmic triglyceride content was observed in electron micrographs of liver sections from mice overexpressing DGAT1 or DGAT2. Overexpression of DGAT1 or DGAT2 resulted in enhanced [³H]glycerol tracer incorporation into triglyceride within cytoplasmic lipids. These results suggest that increasing the cytoplasmic triglyceride pool in hepatocytes does not directly influence VLDL triglyceride or apoB production. In the presence of adequate cytoplasmic lipid stores, factors other than triglyceride synthesis are rate-limiting for VLDL production.

Supplementary key words cholesterol • low density lipoprotein • adenovirus • apolipoprotein B • diacylglycerol • acyl-coenzyme A:diacylglycerol transferase • very low density lipoprotein

Abbreviations: AdmDGAT1 or AdmDGAT2, recombinant adenovirus containing the murine DGAT1 or DGAT2 cDNA; AdNull, recombinant adenovirus containing no transgene; ALT, alanine aminotransferase; apoB, apolipoprotein B; DGAT, acyl-coenzyme A:diacylglycerol transferase; ER, endoplasmic reticulum; GFP, green fluorescent protein; MTP, microsomal triglyceride transfer protein

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