Hepatic VLDL secretion: DGAT1 determines particle size but not particle number which is supported by DGAT2 activity in the absence of DGAT1.

DGAT1 activity is expressed on both aspects of the endoplasmic reticulum (dual membrane-topology) and plays a distinctive role in determining the triglyceride (TAG) content of VLDL particles secreted by the liver. Mice specific DGAT1 ablation in hepatocytes (DGAT1-LKO mice) had the same number of VLDL particles (apoB concentration) in the plasma, but these particles were approximately halve the size of VLDL particles secreted by control mice, and had a proportionately decreased content of TAG, with normal cholesterol and cholesterol ester contents. Analyses of purified microsomal fractions prepared from 16h-fasted control and DAGT1-LKO mice showed that the TAG/protein ratio in the endoplasmic reticulum (ER) was significantly lower in the latter. Electron micrographs of these livers showed that those from DGAT1-LKO mice did not show the increased lipid content of the smooth ER shown by control livers. The effects of DGAT1- and DGAT2-specific inhibitors on apoB secretion by HepG2 cells showed that DGAT1 is not indispensable for apoB secretion, and demonstrated redundancy in the ability of the two enzymes to support apoB secretion. Therefore, our findings show that DGAT1 is essential for the complete lipidation and maturation of VLDL particles within the lumen of the ER, consistent with its dual topology within the ER membrane. In the mouse, DGAT2 can support apoB secretion (particle number) even when TAG availability for full VLDL lipidation is restricted in the absence of DGAT1.