Abstract
Male rats were fed a cholesterol-free diet or the same diet supplemented with either 0.05, 0.1, 0.25, 0.5, 1, or 2% C for 21 days to investigate the effects of cholesterol on secretion of very low density lipoprotein (VLDL). Cholesterol feeding increased plasma and hepatic concentrations of triglyceride (TG) and cholesteryl esters (CE) in a dose-dependent manner. Plasma VLDL and low density lipoprotein (LDL) lipids were elevated by cholesterol feeding, while the high density lipoprotein (HDL) lipids were reduced. The secretion of the VLDL by perfused livers from these cholesterol-fed rats was examined to establish the relationship between the accumulation of lipids in the liver and the concurrent hyperlipemia. Liver perfusions were carried out for 4 h with a medium containing bovine serum albumin (3% w/v), glucose (0.1% w/v), bovine erythrocytes (30% v/v), and a 10-mCi 3H2O initial pulse. Oleic acid was infused to maintain a concentration of 0.6 mM. Hepatic secretion of VLDL-TG, PL (phospholipid), free cholesterol (FC), and CE increased in proportion to dietary cholesterol and was maximal at 0.5% cholesterol in these experiments in which TG synthesis was stimulated by oleic acid. Secretion of VLDL protein and apoB by the perfused liver was also increased. The molar ratios of surface (sum of PL and cholesterol) to core (sum of TG and CE) lipid components of the secreted VLDL, regardless of cholesterol feeding, were the same, as were the mean diameters of the secreted particles. The molar ratios of surface to core lipid of VLDL isolated from the plasma also were not affected by cholesterol feeding. During perfusion with oleic acid of livers from the rats fed the higher levels of cholesterol, the hepatic concentration of CE decreased, while the level of TG was not changed. We conclude that the hypercholesterolemia and hypertriglyceridemia that occur in vivo from cholesterol feeding, concurrent with accumulation of CE and TG in the liver, must result, in part, from increased hepatic secretion of all VLDL lipids and apoB. The VLDL particles produced by the liver of the cholesterol-fed rat are assembled without modification of the surface lipid ratios (PL/FC), but contain a greater proportion of cholesteryl esters compared to triglyceride in the core, because of the stimulated transport of CE from the expanded pool in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
Highlights
Male rats were fed a cholesterol-free diet or the same diet supplemented with either 0.05, 0.1, 0.25, 0.5, 1,or 2% C for 21 days to investigate the effects of cholesterol on secretion of very low density lipoprotein (VLDL)
It is well established that the liver regulates plasma levels of cholesterol and triglyceride (TG) by secretion and transport of these lipids in the VLDL and by removal of lipoproteins by receptor-mediated endocytosis, and that changes in nutritional and hormonal status alter the rate of assembly and secretion of VLDL particles (1-3)
The primary stimulus for formation and secretion of the VLDL is the availability of free fatty acids (FFA) for TG synthesis, it was postulated that the ability of the liver to synthesize and secrete VLDL may be regulated by availability of lipids or apolipoproteins that comprise the surface of the VLDL (4)
Summary
Male Sprague-Dawley rats, (100-125 g) were purchased from Harlan Labs (Indianapolis, IN). Normal male Sprague-Dawley rats were maintained ad libitum on water and the basal diet, supplemented with corn oil to constitute 5% of the diet. After removal of a blood sample from the abdominal aorta, the livers were isolated surgically and perfused in vitro using the recycling perfusion apparatus described previously (15, 16). The livers were generally isolated between 08:OO and 10:OO h and were perfused with a basal medium containing 3 g of bovine serum albumin (BSA)/dl, 100 mg glucose/dl, washed bovine erythrocytes (30% v/v) in Krebs-Henseleit bicarbonate buffer A 60-ml sample of cell-free perfusate was obtained from the perfusate at the end of the experiment and used to isolate the nascent VLDL (VLDL secreted by the perfused liver) by ultracentrifugation, as described previously (18)
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