Effect of experimental nephrosis on hepatic lipoprotein secretion and urinary lipoprotein excretion in rats expressing the human apolipoprotein A-I gene.
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.
Marsh
J B
JB
Medical College of Pennsylvania, Philadelphia, USA.
Diffenderfer
M R
MR
Fisher
E A
EA
Sowden
M
M
Dong
M
M
Paterniti
J R
JR
Burkey
B F
BF
D000818:Animals; D030801:Animals, Genetically Modified; D016632:Apolipoprotein A-I / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism / Q000652:urine; D015870:Gene Expression; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000652:urine*; D008099:Liver / Q000378:metabolism; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010743:Phospholipids / Q000652:urine; D011506:Proteins / Q000378:metabolism; D017393:RNA Editing; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008074:Lipoproteins; D010743:Phospholipids; D011506:Proteins; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases