Cholesterol is required for the secretion of the very-low-density lipoprotein: in vivo studies.

ABSTRACT

Rats were fed for 1 week with a standard chow diet, a diet supplemented with lovastatin (0.1%), or a diet supplemented with both lovastatin and cholesterol (0.1/0.1%), to study effects of depletion of a putative hepatic metabolic pool of cholesterol on secretion of the very-low-density lipoprotein (VLDL) in the intact animal. Triton WR-1339 (50 mg/100 g body wt.) or the 0.9% NaCl vehicle alone was given intravenously via a sacral vein. Treatment with lovastatin decreased the secretion of all plasma VLDL lipids, the average decrease after 2 h for VLDL triacylglycerol, phospholipid, cholesterol and cholesteryl ester being 45%. When both lovastatin and cholesterol were included in the diet, the secretion of VLDL triacylglycerol and phospholipid was similar to that of control animals, while secretion of VLDL cholesterol and cholesteryl ester was increased. Treatment with lovastatin reduced the hepatic concentration of cholesteryl esters 42% without affecting free cholesterol. In separate experiments, in vivo synthesis of cholesterol was determined 1 h after intraperitoneal administration of 3H2O. Incorporation into hepatic and plasma free cholesterol and cholesteryl esters was greater in the rats fed lovastatin than in control animals, concurrent with decreased VLDL secretion. The metabolism of VLDL was determined in vivo by intravenous administration of 125I-VLDL. The fractional clearance rates of 125I-VLDL from the plasma were similar among the three experimental groups. Synthesis of hepatic triacylglycerol from [1-14C]oleate in vivo was similar in all treatment groups; incorporation into plasma triacylglycerol was reduced with lovastatin treatment and reversed partially by inclusion of 0.1% cholesterol in the lovastatin diet. Plasma concentrations of triacylglycerol followed patterns of incorporation of [1-14C]oleate. Triacylglycerol concentration in the liver increased when cholesterol was included in the diet. In companion experiments, incorporation of [1-14C]oleate into perfusate triacylglycerol in vitro was reduced with perfused livers from lovastatin-treated animals. In these experiments, oxidation of fatty acid into CO2 and perchloric acid-soluble counts was not affected by lovastatin, added either to the diet or to the perfusate in vitro. It appears, therefore, that lovastatin does not affect triacylglycerol synthesis or fatty acid oxidation, which per se might reduce formation and secretion of VLDL. These data, therefore, strengthen the hypothesis that reduced availability of cholesterol in a putative hepatic metabolic pool, required for secretion and transport of triacylglycerol in the VLDL, is a factor contributing to decreased secretion of the VLDL.