EFFECT OF EXPERIMENTAL NEPHROSIS ON HEPATIC LIPOPROTEIN SECRETION ANDURINARY LIPOPROTEIN EXCRETION IN RATS EXPRESSING THE HUMAN APOLIPOPROTEIN-A-I GENE

When human apolipoprotein A-I was expressed in transgenic rats, induct ion of the nephrotic syndrome resulted in plasma A-I levels exceeding 10 mg/ml. Plasma lipids were no higher than in non-transgenic nephroti c rats. To explain this, the livers from four groups of rats were perf used: wildtype controls (WC), high expressor human apoA-I transgenic c ontrols (TrGC), wild-type nephrotics (WN), and high expressor transgen ic 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 t o human apoA-I. Compared to the WC group, nephrosis in the WN rats cau sed a 2-fold increase in both d < 1.063 g/ml lipoproteins and HDL secr etion with a 4.6-fold increase in rat apoA-I output. Compared to the T rGC 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 f or 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. Urinar y HDL particles from the TrGN rats did not contain rat apoA-I and aver aged 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 m ature 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 level s in TrGN rats were also not increased may relate to the failure of he patic apoB secretion to increase, which in turn may have been due to s aturation of the protein synthetic capacity by human apoA-I production .-Marsh, J. B., M. R. Diffenderfer, E. A. Fisher, M. Sowden, M. Dong, J. R. Paterniti, and B. F. Burkey. Effect of experimental nephrosis on hepatic lipoprotein secretion and urinary lipoprotein excretion in ra ts expressing the human apolipoprotein A-I gene.