Journal of Lipid Research, Vol 37, 1113-1124, Copyright © 1996 by Lipid Research, Inc.
Effect of experimental nephrosis on hepatic lipoprotein secretion and urinary lipoprotein excretion in rats expressing the human apolipoprotein A-I gene
JB Marsh, MR Diffenderfer, EA Fisher, M Sowden, M Dong, JR Paterniti and BF Burkey
Medical College of Pennsylvania, Philadelphia, USA.
When human apolipoprotein A-I was expressed in transgenic rats, induction
of the nephrotic syndrome resulted in plasma A-I levels exceeding 10 mg/ml.
Plasma lipids were no higher than in non-transgenic nephrotic rats. To
explain this, the livers from four groups of rats were perfused: wild-type
controls (WC), high expressor human apoA-I transgenic controls (TrGC),
wild-type nephrotics (WN), and high expressor transgenic nephrotics (TrGN).
Compared to the WC group, TrGC rats secreted the same amount of d <
1.063 g/ml lipoproteins but 50% more high density lipoprotein (HDL), with a
5-fold increase in total apoA-I output due to human apoA-I. Compared to the
WC group, nephrosis in the WN rats caused a 2-fold increase in both d <
1.063 g/ml lipoproteins and HDL secretion with a 4.6-fold increase in rat
apoA-I output. Compared to the TrGC group, nephrosis in the TrGN rats did
not increase d < 1.063 g/ml lipoprotein secretion, but caused a 50%
increase in HDL secretion and a 6-fold increase in human apoA-I output. The
hepatic levels of mRNA for apoB and for HMG-CoA reductase, as well as the
degree of apoB mRNA editing, were unchanged. Examination of the perfusate
HDL by electron microscopy revealed spherical particles averaging 30 nm in
diameter in the WC and WN rats and 17 and 20 nm in the TrGC and TrGN rats.
Urinary HDL particles from the TrGN rats did not contain rat apoA-I and
averaged 8.2 nm versus 11 nm in the WN rats. We conclude that the size of
the nascent HDL, and subsequently of the mature HDL, is determined by the
primary structure of apoA-I. In the TrGN rats, the heterogeneous mature HDL
has a population of smaller human HDL which is more readily lost in the
urine, accounting for the failure of plasma HDL levels to rise above those
in TrGC rats. The fact that plasma triglyceride levels in TrGN rats were
also not increased may relate to the failure of hepatic apoB secretion to
increase, which in turn may have been due to saturation of the protein
synthetic capacity by human apoA-I production.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
