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The biology of the low-density lipoprotein (LDL) receptor has been examined in detail, and a paradigm for LDL metabolism has evolved from comparative studies of cholesterol metabolism in a variety of cells cultured from normal individuals and subjects with familial hypercholesterolemia (FH). Cultured cells from patients with homozygous FH lack a functional LDL receptor and show diminished LDL clearance, induction of the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, increased cholesterol synthesis, decreased cholesterol ester production, and depleted cholesterol ester stores. The observed decrease in the fractional catabolic rate (FCR) of LDL is attributed to the mutated LDL receptor gene. However, in the experimental animal model of this disease, the Watanabe heritable hyperlipidemic (WHHL) rabbit, cholesterol ester stores are increased, while hepatic cholesterol synthesis is decreased. Furthermore, in humans HMG-CoA reductase is suppressed, and the LDL apolipoprotein (apo) B production rate is increased in patients with FH. These findings raise questions about the adequacy of the paradigm in understanding hepatic cholesterol metabolism in vivo. In humans, apoB metabolism is believed to be principally determined by the liver, where apoB is both synthesized and catabolized. Assuming the neutral lipid content of the liver is the major determinant of apoB metabolism, we postulated that the changes in apoB metabolism in FH are predictable when based on the assumption of an increase in hepatic cholesterol and cholesterol ester content, as observed both in the WHHL rabbit and in humans. We examined this hypothesis in vivo in patients with heterozygous FH by using tracer kinetic methodology and have used similar data from normal and hypertriglyceridemic (HTG) subjects as controls. Whereas normal and HTG subjects secrete apoB primarily as large, triglyceride-enriched very-low-density lipoprotein (VLDL), heterozygous FH patients have an absolute decrease in apoB production and secrete almost 40% of apoB as smaller intermediate-density lipoprotein (IDL)/LDL. In normal humans, about half of secreted apoB is catabolized rather than being converted to LDL. In HTG subjects two thirds of apoB follows this same route, by which VLDL remnants remaining after triglyceride hydrolysis are largely returned to the liver. In contrast, in FH subjects secreted apoB is fully converted to LDL. Thus, although total apoB secretion is reduced in FH subjects, total LDL production is greater than in either normal or HTG subjects. Under basal conditions the elevated LDL in heterozygous FH is due to both decreased LDL receptor-mediated catabolism and increased LDL production. However, the number of LDL receptors actually expressed is suppressed below the number of potentially functional receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

ApoB metabolism in familial hypercholesterolemia. Inconsistencies with the LDL receptor paradigm.