APO-B METABOLISM IN FAMILIAL HYPERCHOLESTEROLEMIA - INCONSISTENCIES WITH THE LDL RECEPTOR PARADIGM

The biology of the low-density lipoprotein (LDL) receptor has been exa mined in detail, and a paradigm for LDL metabolism has evolved from co mparative studies of cholesterol metabolism in a variety of cells cult ured from normal individuals and subjects with familial hypercholester olemia (FH). Cultured cells from patients with homozygous FH lack a fu nctional LDL receptor and show diminished LDL clearance, induction of the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, incre ased cholesterol synthesis, decreased cholesterol ester production, an d depleted cholesterol ester stores. The observed decrease in the frac tional catabolic rate (FCR) of LDL is attributed to the mutated LDL re ceptor gene. However, in the experimental animal model of this disease , the Watanabe heritable hyperlipidemic (WHHL) rabbit, cholesterol est er stores are increased, while hepatic cholesterol synthesis is decrea sed. Furthermore, in humans HMG-CoA reductase is suppressed, and the L DL apolipoprotein (apo) B production rate is increased in patients wit h FH. These findings raise questions about the adequacy of the paradig m 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 predicta ble when based on the assumption of an increase in hepatic cholesterol and cholesterol ester content, as observed both in the WHHL rabbit an d in humans. We examined this hypothesis in vivo in patients with hete rozygous 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, trigl yceride-enriched very-low-density lipoprotein (VLDL), heterozygous FH patients have an absolute decrease in apoB production and secrete almo st 40% of apoB as smaller intermediate-density lipoprotein (IDL)/LDL. In normal humans, about half of secreted apoB is catabolized rather th an being converted to LDL. In HTG subjects two thirds of apoB follows this same route, by which VLDL remnants remaining after triglyceride h ydrolysis are largely returned to the liver. In contrast, in FH subjec ts secreted apoB is fully converted to LDL. Thus, although total apoB secretion is reduced in FH subjects, total LDL production is greater t han in either normal or HTG subjects. Under basal conditions the eleva ted LDL in heterozygous FH is due to both decreased LDL receptor-media ted catabolism and increased LDL production. However, the number of LD L receptors actually expressed is suppressed below the number of poten tially functional receptors. Support for this conclusion is derived fr om the findings that when diets or drugs are administered that decreas e the hepatic concentration of cholesterol esters, the FCR of LDL incr eases to normal values, reflecting an increase in expressed hepatic LD L receptors. Apparently in heterozygous patients these receptors are n ormally suppressed below the upper limit that can be expressed by a si ngle functional gene. In summary, three major changes occur in apoB me tabolism in heterozygous FH subjects: (1) a decrease in total and VLDL apoB secretion with a shift to the production of smaller IDL/LDL spec ies; (2) the loss of the catabolic pathway for VLDL apoB remnants; and (3) a reversible decrease in the FCR of LDL apoB, which is normalized by dietary or drug perturbations that reduce hepatic cholesterol. All these findings are explainable as an adaptation to an increase in hep atic cholesterol ester content but not by the classic LDL receptor par adigm. How this pathophysiology arises from the mutation of the LDL re ceptor gene is unknown.