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Plasma low density lipoprotein (LDL) kinetics and their relation to plasma very low density lipoprotein (VLDL) and LDL composition were determined in patients with familial combined hyperlipidemia (FCHL) of varying lipoprotein phenotypes. In both Type II and IV subjects, LDL apolipoprotein B (apo B) synthesis was greater than normal. In Type IV, the VLDL triglyceride/apo B ratio was normal and almost all of the LDL apo B was derived from VLDL. LDL cholesterol/apo B ratio was diminished and LDL apo B fractional catabolic rate (FCR) was sufficiently increased to prevent a rise in plasma LDL concentration. In Type II, VLDL triglyceride/apo B was reduced and 14% to 50% of the LDL was formed by direct synthesis. LDL cholesterol/apo B was normal and LDL apo B FCR was lower than in Type IV subjects. In four patients whose plasma lipid levels became normal with carbohydrate restriction and intake of a fibric acid derivative, plasma VLDL and LDL composition and LDL kinetic measurements remained unchanged. By contrast, VLDL triglyceride-apo B decreased and direct LDL synthesis increased in four patients whose phenotype changed to Type IIa. LDL cholesterol/apo B also increased and LDL FCR declined. Among patients with FCHL, significant correlations between VLDL triglyceride/apo B, LDL apo B derived by direct synthesis, LDL cholesterol/apo B, and LDL apo B FCR were found. Thus, increased apo B synthesis is a characteristic feature of FCHL. The phenotypic expression is determined by the availability of triglyceride for hepatic coupling to apo B which could influence the source, composition, and removal rate of circulating LDL. Despite normalization of their plasma lipid levels, some patients continued to show the compositional and kinetic features of FCHL.

Plasma low density lipoprotein (LDL) transport kinetics were determined from the disappearance of 125I-LDL injected into age- and weight-matched groups of 13 normal subjects, 20 mild diabetics, and 8 moderately severe diabetic patients (fasting plasma glucose less than 150 and greater than 150 mg/100 ml, respectively). In mild diabetics, LDL apo-lipoprotein-B (apo-B) synthetic rate (SR) was significantly greater than normal. The fractional catabolic rate (FCR), however, was also increased so that plasma LDL concentration remained normal. In moderately severe diabetics, LDL SR was normal but FCR was reduced resulting in increased plasma LDL cholesterol and apo-B concentrations. In normal subjects, moderate obesity was associated with increased LDL secretion. In diabetic subjects, however, changes in LDL turnover were of equal magnitude in obese and nonobese patients. In normolipemic and hyperlipemic mild diabetic subjects with equal degrees of glucose intolerance, both LDL apo-B SR and FCR were greater than normal. The magnitude of these increases, however, was lower in the hyperlipemic individuals. Stepwise regression analysis revealed that both LDL SR and FCR correlated positively and linearly with insulin response to glucose loading, but negatively and curvilinearly with fasting plasma glucose and glucose response. We propose that in noninsulin-dependent diabetes, mild hyperglycemia is accompanied by increased LDL turnover, despite normal plasma LDL levels, whereas moderately severe hyperglycemia is associated with decreased LDL catabolism, resulting in increased plasma LDL levels. These changes cannot be attributed to the presence of obesity or hypertriglyceridemia, and may relate to varying degrees of insulin resistance and decreased insulin secretion affecting plasma very low density lipoprotein (VLDL) secretion, VLDL conversion to LDL, and LDL catabolism. Both increased LDL turnover in mild diabetes and delayed removal of LDL in moderately severe diabetes could increase cholesterol ester availability to peripheral tissues, and may result in an increased risk of atherosclerosis.

Turnover kinetics of triglycerides (TG) and apolipoprotein-B (apo-B) of plasma very low density lipoprotein (VLDL) and their relationship to plasma VLDL composition and VLDL apo-B conversion to low density lipoprotein (LDL) were determined in age and weight-matched groups of normolipemic (NL) healthy subjects, patients with familial combined hyperlipidemia (FCHL) and patients with familial hypertriglyceridemia (FHTG). In NL subjects, a significant correlation as observed between VLDL TG or VLDL apo-B turnover rate and its circulating mass, suggesting that the plasma level of VLDL was determined by the secretion rate of VLDL TG and apo-B. The positive significant correlation between VLDL TG and apo-B also suggests that the production of these moieties was integrated at the synthetic and/or secretory sites to maintain the ratio of TG to apo-B in plasma VLDL. In moderately obese NL subjects, proportionate increases in VLDL TG and apo-B turnover rates resulted in enhanced secretion of VLDL particles. Both groups with genetic hypertriglyceridemia had increased VLDL TG and VLDL apo-B turnover rates. This increase accounted for the increase in circulating VLDL TG and apo-B mass. In patients with FCHL, turnover rates of VLDL TG and apo-B were equally increased, hence, the ratios between major VLDL constituents were within normal limits. On the other hand, the increase in VLDL TG turnover in patients with FHTG was disproportionately greater than that of apo-B resulting in a higher ratio of TG to other VLDL components. In NL subjects, approximately 72% of VLDL apo-B released into plasma was converted to LDL. This conversion correlated positively with VLDL apo-B turnover rate and inversely with VLDL TG turnover rate. Formation of LDL from VLDL was significantly greater in the obese individuals. In FCHL, conversion of VLDL to LDL represented the major pathway for VLDL apo-B catabolism. The increased VLDL apo-B load was predominantly catabolized to LDL. The greater increase in VLDL TG turnover relative to apo-B in FHTG, on the other hand, resulted in a smaller fraction of VLDL apo-B recovered in LDL, most of the VLDL apo-B being removed via a pathway that did not involve this conversion. We conclude that the composition and metabolic fate of plasma VLDL may be greatly influenced by the secretion rates of VLDL TG and apo-B. If VLDL conversion to LDL and the subsequent catabolism of the latter provides a major route for delivery of cholesterol ester to peripheral tissues, then the increased LDL production in FCHL compared to FHTG may account for a higher cardiovascular risk.