Low density lipoprotein metabolism in familial combined hyperlipidemia. Mechanism of the multiple lipoprotein phenotypic expression.

Abstract

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 syntheseis increased in four patients whose phenotype changed to Type Ha. LDL cholesterol/apo B also increased and LDL FCR declined. Among patients with FCHL, significant correleations 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. (Arteriosclerosis 4:614-624, November/December 1984)

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

“…In these individuals, triglyceride-enriched VLDL (49,50) accumulate in plasma and turnover studies show reduced removal of VLDL triglycerides (51,52). This contrasts with turnover studies in hypertriglyceridemic obese individuals, which indicate a major increase in VLDL triglyceride production (51,53,54), and studies in patients with familial combined hyperlipidemia which indicate increased VLDL apo B production rate (51,(55)(56)(57) and increased numbers of normal-sized VLDL particles (51,52). Thus the HuCIIITg mouse mainly resembles primary familial hypertriglyceridemia and this study provides a possible mechanism for this human condition.…”

Familial hypoalphalipoproteinemia in premature coronary artery disease.

“…The current data suggest that hepatic oversecretion of apoB underlies most cases of FCH (or hyperapoB). 15 - 21 The underlying metabolic defects in FCH are now better understood. There is enough evidence to suggest that it shares many biochemical and physiological features of familial hyperapoB so that the two can be considered part of the same syndrome, characterized by increased hepatic oversecretion of apoB-containing particles.…”

Role of lipoprotein lipase in the regulation of high density lipoprotein apolipoprotein metabolism. Studies in normal and lipoprotein lipase-inhibited monkeys.

“…Hypertriglyceridemic humans often have an increased LDL FCR (49,50) and a metabolic defect that results in overproduction of VLDL and apoprotein B (the major structural protein of both VLDL and LDL) (51)(52)(53). Despite the expanded pool of VLDL which may compete with LDL for binding to the LDL receptor (54), LDL FCR is increased, suggesting that these patients may have a defect which increases LDL receptor activity in addition to or as a result of the regulatory defect in apo B production.…”