The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice

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Mensenkamp, A.R.

Luyn, M.J.A. van

Havinga, R.

Teusink, B.

Waterman, I.J.

Mann, C.J.

Elzinga, B.M.

Verkade, H.J.

Zammit, V.A.

Havekes, L.M.

Shoulders, C.C.

Kuipers, F.
Background/Aims Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG. Methods and 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. © 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Chemicals / CAS: diacylglycerol acyltransferase, 9029-98-5; Apolipoproteins E; Carrier Proteins; Lipoproteins, VLDL; microsomal triglyceride transfer protein; Triglycerides; very low density lipoprotein triglyceride
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Biomedical ResearchApolipoprotein EFatty liverHyperlipidemiaMTPTriglyceridesVLDL secretionapolipoprotein Ediacylglycerol acyltransferasemicrosomal triglyceride transfer proteintriacylglycerolvery low density lipoproteinanimal cellanimal tissuebioaccumulationcell transportcontrolled studycytosolexperimental modelGolgi complexhomeostasisknockout mouselipid analysislipid transportlipogenesislipoprotein synthesisliver cellmousenonhumanwild typeAnimalsApolipoproteins EBiological Transport, ActiveCarrier ProteinsEndoplasmic ReticulumHepatocytesLipoproteins, VLDLMaleMiceMice, Inbred C57BLMice, KnockoutMicroscopy, ElectronTriglycerides
TNO Identifier
237692
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ISSN
01688278
Source
Journal of Hepatology, 40(4), pp. 599-606.
Pages
599-606
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