The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice.
OBJECTIVE
Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG.


RESULTS
We examined the effects of apoE-deficiency on intracellular lipid homeostasis and secretion of triglycerides (TG). We show that intracellular TG turnover and activities of diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer protein (MTP) are similar in Apoe(-/-) and wild type mice. In addition, apoB synthesis was not decreased in Apoe(-/-) cells. Thus, the accumulation of lipid in these cells is not attributable to perturbed TG turnover, apoB synthesis, and the activities of DGAT and MTP. Inhibition of MTP had a more profound impact on the secretion of VLDL-TG from wild type hepatocytes than Apoe(-/-) hepatocytes, indicating that MTP was more limiting for the production of VLDL-TG from wild type cells. In marked contrast to the MTP-deficient model of fatty liver, electron microscopy of lipid-stained liver sections of Apoe(-/-) mice revealed an accumulation of lipid in numerous small, putative ER-derived vesicles and in the cytosol. No abnormalities were observed in the Golgi of Apoe(-/-) mice.


CONCLUSIONS
These results suggest that the removal of lipids from the early or intermediary compartments of the secretory pathway of hepatocytes is impaired in Apoe(-/-) mice.
Mensenkamp
Arjen R
AR
Department of Cell Biology, Faculty of Medical Sciences, University Hospital Groningen, 9713 GZ Groningen, The Netherlands. a.r.mensenkamp@writeme.com
Van Luyn
Marja J A
MJ
Havinga
Rick
R
Teusink
Bas
B
Waterman
Ian J
IJ
Mann
Christopher J
CJ
Elzinga
Baukje M
BM
Verkade
Henkjan J
HJ
Zammit
Victor A
VA
Havekes
Louis M
LM
Shoulders
Carol C
CC
Kuipers
Folkert
F
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000648:ultrastructure; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D014280:Triglycerides / Q000378:metabolism*
D001057:Apolipoproteins E; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride