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It is generally accepted that hepatic secretion of apoprotein (apo) B-containing lipoproteins is substantially increased in nephrosis. To elucidate the mechanisms for the oversecretion of apo B, we investigated the effect of a various concentration of albumin on apo B kinetics in the absence or presence of oleate in Hep G2 cells. Hep G2 cells were labeled with [3H]-leucine in leucine-free medium containing 0, 1.5, 3.0 or 4.5% BSA for 180 minutes, and the secreted radiolabeled apo B, apo A1 and albumin were isolated by immunoprecipitation and counted. The secretions of apo B and albumin were suppressed by BSA (bovine serum albumin) in a dose-dependent manner, but the secretion of apo A1 was not suppressed significantly. Oleate (0.4 mM) increased the rate of apo B secretion by 2.5-fold when oleate was bound to 1.5% BSA, but at higher concentrations of BSA (3.0 or 4.5%), apo B secretion was less responsive to oleate. A pulse-chase study indicated that early apo B degradation was significantly suppressed in cells incubated with lower concentrations of BSA (0 or 1.5% BSA), thereby rapidly stimulating apo B secretion. Oleate (0.4 mM) potently inhibited apo B degradation when oleate was bound to 1.5% BSA, whereas the inhibition was not observed when oleate was bound to 4.5% BSA. Intracellular albumin synthesis was stimulated in BSA-free medium, but intracellular decay of albumin was essentially unaffected by concentration of BSA. Similar to BSA, a higher concentration of dextran (3.0 or 4.5%) reduced apo B secretion, and this was the result of increased early apo B degradation in the cells. These results indicate that reduced albumin suppresses intracellular apo B degradation, and the inhibition of apo B degradation by oleate is manifested only at a low concentration of albumin. Therefore, the present study suggests that free fatty acids bound to low concentration of albumin in the circulating plasma play an important role on hepatic oversecretion of apo B-containing lipoprotein in hypoalbuminemic state, such as nephrotic syndrome.

The effects of fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the hyperhpidemia associated with nephrosis were studied. Nephrotic rats, induced by a single intraperitoneal injection of puromycin aminonucleoside (100 mg/kg body weight), had significantly higher plasma triglyceride (TG), total cholesterol and apoprotein (apo) B concentrations than controls. Fluvastatin was administrated as a 0.01% solution in drinking water for 14 days to either normal control or nephrotic rats. Concentrations of TG and apo B in plasma, and very low-density lipoprotein (VLDL) in nephrosis were completely normalized by the treatment with fluvastatin, but concentrations of cholesterol in plasma and each lipoprotein fraction were not altered by the treatment. The ratio of apo E to C in VLDL was significantly decreased in nephrotic rats, but the fluvastatin treatment increased this ratio. TG secretion rate estimated by the Triton WR1339 method was significantly increased in nephrotic rats, but was normalized by fluvastatin. Percent composition of TG in newly secreted VLDL particles in post-Triton plasma was not decreased by fluvastatin treatment, suggesting that the number of newly secreted VLDL particles was reduced by the treatment. Postheparin plasma lipolytic activities were not affected by the fluvastatin treatment. These results demonstrate that fluvastatin can effectively ameliorate the high concentration of VLDL by suppressing the hepatic secretion in nephrotic rats, and suggest that an inhibition of cholesterol biosynthesis suppresses VLDL secretion from the liver.

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