Short-term overexpression of DGAT1 or DGAT2 increases hepatic triglyceride but not VLDL triglyceride or apoB production.
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 [(3)H]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.
Millar
John S
JS
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA. jsmillar@mail.med.upenn.edu
Stone
Scot J
SJ
Tietge
Uwe J F
UJ
Tow
Bryan
B
Billheimer
Jeffrey T
JT
Wong
Jinny S
JS
Hamilton
Robert L
RL
Farese
Robert V
RV
Rader
Daniel J
DJ
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis*; D051048:Diacylglycerol O-Acyltransferase / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013347:Subcellular Fractions; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism*
D001055:Apolipoproteins B; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D051048:Diacylglycerol O-Acyltransferase