Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E- deficient mouse hepatocytes

F Kuipers*, M. C. de Jong, YG Lin, M van Eck, R Havinga, Vincent Bloks, HJ Verkade, MH Hofker, H Moshage, TJC van Berkel, RJ Vonk, LM Havekes

*Corresponding author for this work

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Abstract

To explore mechanisms underlying triglyceride (TG) accumulation in livers of chow-fed apo E-deficient mice (Kuipers, F., J.M. van Ree, M.H. Hofker, H. Welters, G. In't Veld, R.J. Vonk, H.M.G. Princen, and L.M. Havekes, 1996. Hepatology. 24:241-247), we investigated the effects of apo E deficiency on secretion of VLDL-associated TG (a) in vivo in mice, (b) in isolated perfused mouse livers, and (c) in cultured mouse hepatocytes. (a) Hepatic VLDL-TG production rate in vivo, determined after Triton WR1339 injection, was reduced by 46% in apo E-deficient mice compared with controls. To eliminate the possibility that impaired VLDL secretion is caused by aspecific changes in hepatic function due to hypercholesterolemia, VLDL-TG production rates were also measured in apo E-deficient mice after transplantation of wild-type mouse bone marrow. Bone marrow-transplanted ape E-deficient mice, which do not express ape E in hepatocytes, showed normalized plasma cholesterol levels, but VLDL-TG production was reduced by 59%. (b) VLDL-TG production by isolated perfused livers from apo E-deficient mice was 50% lower than production by livers from control mice. Lipid composition of nascent VLDL particles isolated from the perfusate was similar for both groups. (c) Mass VLDL-TG secretion by cultured ape E-deficient hepatocytes was reduced by 23% compared with control values in serum-free medium, and by 61% in the presence of oleate in medium (0.75 mM) to stimulate lipogenesis. Electron microscopic evaluation revealed a smaller average size for VLDL particles produced by apo E-deficient cells compared with control cells in the presence of oleate (38 and 49 nm, respectively). In short-term labeling studies, apo E-deficient and control cells showed a similar time-dependent accumulation of [H-3]TG formed from [H-3]glycerol, yet secretion of newly synthesized VLDL-associated [H-3]TG by ape E-deficient cells was reduced by 60 and 73% in the absence and presence of oleate, respectively, We conclude that apo E, in addition to its role in lipoprotein clearance, has a physiological function in the VLDL assembly-secretion cascade.

Original languageEnglish
Pages (from-to)2915-2922
Number of pages8
JournalThe Journal of Clinical Investigation
Volume100
Issue number11
DOIs
Publication statusPublished - 1-Dec-1997
Event69th Annual Scientific Session of the American-Heart-Association -
Duration: 9-Nov-199616-Nov-1996

Keywords

  • transgenic mice
  • lipoproteins
  • liver
  • cholesterol
  • apolipoprotein B
  • B-CONTAINING LIPOPROTEINS
  • BONE-MARROW TRANSPLANTATION
  • TRANSFER PROTEIN
  • HEPG2 CELLS
  • SEVERE HYPERCHOLESTEROLEMIA
  • TRANSGENIC MICE
  • LIVER-CELLS
  • RAT-LIVER
  • ATHEROSCLEROSIS
  • CHOLESTEROL

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