Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol.

Abstract

A B S T R A C T Nonhuman primates consuming diets containing cholesterol develop coronary artery atherosclerosis that we have found to be highly correlated with an increase in the size and cholesteryl ester content of plasma low density lipoproteins (LDL). The present studies were designed to determine whether the enlarged plasma LDL are produced directly by the liver of cholesterol-fed monkeys. African green monkeys were fed a diet containing 40% of calories as butter fat and either 0.16 mg cholesterol/kcal (control diet) or 0.78 mg cholesterol/kcal (test diet). The livers of these monkeys were perfused by recirculation with a lipoprotein-free medium for 4 h. The rate of accumulation of perfusate cholesterol was linear and greater in liver perfusates from test diet-fed vs. control diet-fed monkeys and was positively correlated with both the plasma cholesterol concentration and LDL size in the donor animal. All perfusate d < 1.063 g/ ml lipoprotein subfractions from livers of test diet-fed monkeys were enriched in cholesteryl ester severalfold over the corresponding subfractions from control dietfed monkeys and contained only the larger form of apolipoprotein B typical of plasma LDL. However, the perfusate lipoproteins in the LDL density range did not have an average size or composition typical of LDL from plasma. Rather, they were relatively enriched in phospholipid and unesterified cholesterol and were deficient in cholesteryl esters. In addition, perfusate high density lipoproteins were discoidal particles. These data show that the enzyme lecithin:cholesterol acyltransferase (LCAT) was essentially inactive in Received for publication 20 December 1982 and in revised form 9 March 1983. these perfusates and, as a result, the dietary cholesterol-induced enrichment of perfusate d < 1.063 g/ml lipoproteins with cholesteryl esters probably resulted from increased hepatic secretion of cholesteryl esters and not from modification of lipoproteins by LCAT during recirculating perfusion. In spite of this increase, enlarged cholesteryl ester-rich LDL were not found in the perfusate, suggesting that large molecular weight plasma LDL are not directly secreted by the liver but instead probably result from further intravascular metabolism of cholesteryl ester-enriched hepatic precursor lipoproteins.

Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding.

“…Although the present data and that of Kesaniemi et al (32) have provided direct evidence for the independent production of LDL in normolipidemic humans, numerous studies in experimental animals or in isolated cells in culture have previously documented the liver's ability to secrete LDL-sized lipoproteins (34)(35)(36)(37)(38)(39). Studies have shown that the extent of hepatic LDL and VLDL secretion is dependent on the lipid status of the liver.…”

Metabolic origins and clinical significance of LDL heterogeneity

“…In rats, kinetic studies have shown that larger LDLs (S f [5][6][7][8][9][10][11][12] are derived via a VLDL-IDL metabolic cascade, but small dense LDLs (S f 0-5), which comprise 65% of total LDL mass, do not appear to derive from this pathway (53). In monkeys, it has been reported that the metabolic behavior of LDL derived from endogenously radiolabeled hepatic lipoprotein precursors often differs from that of radiolabeled autologous plasma LDL (54,55). Kinetic analysis and studies involving nascent lipoproteins from perfused livers (55,56) suggested that plasma LDL in these monkeys may be derived from a variety of precursors, with each source giving rise to metabolically (and possible physically) distinct LDL particles.…”

“…In monkeys, it has been reported that the metabolic behavior of LDL derived from endogenously radiolabeled hepatic lipoprotein precursors often differs from that of radiolabeled autologous plasma LDL (54,55). Kinetic analysis and studies involving nascent lipoproteins from perfused livers (55,56) suggested that plasma LDL in these monkeys may be derived from a variety of precursors, with each source giving rise to metabolically (and possible physically) distinct LDL particles. In a spontaneously hypercholesterolemic strain of pigs, two metabolically distinct LDL subclasses have been characterized: the larger, more buoyant species appears to accumulate as a results of both increased production and reduced receptor clearance resulting from an apoB mutation (57).…”

“…have suggested that hepatic apoB is secreted throughout the VLDL-IDL-LDL particle spectrum (60)(61)(62). Direct production of LDL has been reported in kinetic analyses in humans (60), in perfused livers of experimental animals (55,(63)(64)(65), and cardiac tissue (66). Using a trideuterated leucine tracer and analysis with a multicompartmental model which allowed input into each fraction, Packard et al found substantial input of apoB into IDL and LDL, which was inversely related to plasma triglycerides (67).…”

Effects of saturated and polyunsaturated dietary fat on the concentrations of HDL subpopulations in African green monkeys.

“…33 Such lipcproteins are not typically observed in plasma because the plasma enzyme lecithin cholesterol acyltransferase (LCAT) is thought to rapidly mediate the esterification of the free cholesterol in the surface of the precursor particles, 29 with the formation of spherical particles typical of plasma HDL. Particles with the characteristics of HDL precursors, however, have been observed in medium following perfusion of rat 34 and African green monkey livers 35 '…”