Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") in familial combined hyperlipidemia.
Familial combined hyperlipidemia (FCHL) is a heterogeneous genetic disorder characterized by multiple lipoprotein phenotypes. The genetic defect is unknown, although linkage to the region of the apolipoprotein (apo) A-I-apoC-III-apo A-IV gene cluster on chromosome 11 has been suggested. The metabolic abnormality in many affected individuals is overproduction of apoB-containing lipoproteins causing elevated levels of plasma cholesterol, triglycerides, or both. Low levels of high-density lipoprotein (HDL) cholesterol and an abundance of dense low-density lipoprotein (LDL) particles are other features contributing to the high association of this disorder with premature coronary artery disease. Many affected individuals need drug therapy to lower their lipid levels. The hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins," offer a potent therapeutic option in patients with FCHL. These drugs significantly decrease levels of total cholesterol, LDL cholesterol, and apoB, although their effects on HDL cholesterol and triglycerides are limited. The mechanisms by which statins exert their beneficial effects in patients with FCHL remain controversial. We studied 7 patients with FCHL and 5 genetically uncharacterized patients with mixed lipemia during treatment with pravastatin 20 mg/day. Metabolic parameters of very-low-density lipoprotein (VLDL)-apoB and LDL-apoB were studied using endogenous labeling with stable isotopes. In all patients pravastatin caused an increase in fractional catabolic rates of LDL-apoB without a significant effect on the production rates of apoB-containing lipoproteins. We cannot exclude the possibility that higher doses of statins may decrease VLDL and LDL production.
Schonfeld
G
G
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.
Aguilar-Salina
C
C
Elias
N
N
D000818:Animals; D001053:Apolipoproteins / Q000097:blood; D001055:Apolipoproteins B / Q000378:metabolism; D001056:Apolipoproteins C / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006950:Hyperlipidemia, Familial Combined / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D005810:Multigene Family
D001053:Apolipoproteins; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL