Ab btract. The effects of experimental nephrosis in rats, produced by puromycin aminonucleoside, include an elevation of plasma levels of all lipoprotein density classes and the appearance of high density lipoprotein (HDL) rich in apoprotein (apo) A-I and deficient in apo A-IV and apo E. The hyperlipoproteinemia is associated with an increase in hepatic synthesis of lipoproteins. The possible role of decreased very low density lipoprotein (VLDL were obtained from nonfasting animals by ultracentrifugation at d 1.006 and included chylomicrons) catabolism and its relationship to the apolipoprotein composition of nephrotic high density lipoproteins (1.063 < d < 1.210, or 1.072 < d < 1.210 [HDL]) was explored.When 125I-VLDL was injected, the faster plasma clearance of lower molecular weight apolipoprotein B (apo BL) compared with that of higher molecular weight apo BH which is seen in normal rats was not observed in nephrotic rats. Less labeled phospholipid, apo C, and apo E were transferred from VLDL to higher lipoprotein density classes. Heparin-releasable plasma lipoprotein lipase and hepatic lipase activities were decreased by 50% in nephrotic rats compared with pair-fed controls. Perfusion of livers with medium that contained heparin released 50% less lipase activity in nephrotic rats than in controls.When heparin was injected intravenously, significant decreases in plasma levels of triglycerides and significant increases in levels of free fatty acids were observed in both groups of animals. In the nephrotic rats, 86% of the free fatty acids were in the lipoprotein fractions, as compared with 16% in the controls. Heparin treatment A portion of this work has been presented in abstract form

When hepatocytes were cultured for 24 h in the presence of forskolin (10(-4) mol l-1) or isobutylmethylxanthine (IBMX, 10(-3) mol l-1), the intracellular cAMP concentration peaked (320-380 pmol mg-1 protein) after 10-20 min of culture. This increase was accompanied by a decrease in the secretion of triacylglycerol, cholesterol and apoprotein B associated with VLDL. After 4 h cAMP levels had returned almost to basal values but the inhibition of VLDL secretion persisted. There was a small intracellular accumulation of triacylglycerol but not of apoprotein B. Addition of forskolin and IBMX together led to a further increase in intracellular cAMP and a further suppression of VLDL output. Similar effects on the secretion of VLDL were also observed after addition of Bt2cAMP. Exposure of cell cultures to glucagon (10(-7) mol l-1) for only 10 min raised cellular cAMP levels to > 200 pmol mg-1 protein, and suppressed VLDL secretion during the next 24 h to < 40% of control. All of the substances tested inhibited de novo synthesis of fatty acids but had little or no effect on cholesterol synthesis and did not inhibit oleate esterification to triacylglycerol. The cAMP-dependent protein kinase antagonist Rp-cAMPS prevented suppression of VLDL triacylglycerol secretion induced by glucagon (10(-7) mol l-1) and abolished glucagon-induced ketogenesis. Rp-cAMPS also inhibited Bt2cAMP (7.5 x 10(-6) mol l-1)-induced suppression of VLDL secretion and enhancement of ketogenesis. It is concluded that rat hepatic VLDL metabolism can be regulated by cAMP and cAMP-dependent protein kinases, and that the initial transient rise in cellular cAMP levels induced by glucagon is sufficient to maintain a long-term inhibitory effect on assembly and secretion of VLDL.

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