Familial Combined Hyperlipidemia and Insulin Resistance

Abstract

F amilial combined hyperlipidemia (FCHL), originally identified by Goldstein et al, 1 Rose et al, 2 and Nikkila et al 3 in the early 1970s, is a metabolic defect in lipoprotein metabolism that is associated with a predominance of small, dense LDL particles and appears to be a consequence of hepatic overproduction of apolipoprotein B-100 (apoB-100). Characteristic lipoprotein abnormalities include increases in apoB with variable manifestations of hyperlipidemia, including hypertriglyceridemia and/or increases in LDL cholesterol. Although FCHL has historically been viewed as a monogenic disorder, more recent analyses suggest that the disorder may be predicted by a threshold model in which apoB level genotype and LDL subclass phenotype interact to increase the risk of FCHL. 4 Despite the fact that FCHL appears to be the most common genetic cause of hyperlipidemia and almost certainly predisposes to more coronary heart disease (CHD) events than any other known genetic disorder, the mechanism for increases in hepatic overproduction of apoB-containing lipoproteins remains unclear. Moreover, although genes have been identified that may contribute to the dyslipidemia of FCHL, 5 a genetic explanation for the increases in apoB production is lacking. See page 567Insulin resistance is also associated with small, dense LDL and lipoprotein abnormalities, including hypertriglyceridemia and/or reductions in HDL cholesterol. However, increases in apoB are not distinctive of reductions in insulin action. Presently, much of the evidence links the metabolic abnormalities of the insulin resistance syndrome to modifications of body fat distribution, ie, relative increases in intraabdominal fat (IAF). 6 Presently, it remains unclear whether FCHL is accompanied by increases in IAF; however, patients with FCHL are insulin resistant. 7,8 Thus, it is important to discern the relative interdependence of insulin resistance and apoB, both potential explanations for the increase in CHD risk in FCHL patients.The study reported by Purnell et al 9 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology addresses this relationship in a small number (nϭ11, 6 men and 5 women) of well-characterized and zealously studied subjects with FCHL and age-and/or age-and weight-matched controls. Unfortunately, only 1 of the 22 age-and weightmatched controls was female. When compared with agematched controls, FCHL subjects were again demonstrated to be insulin resistant, but not when compared with age-and weight-matched controls who also had increases in IAF. Importantly, the insulin resistance or amount of IAF in FCHL subjects failed to explain the levels of apoB, which were higher for any level of insulin action in FCHL subjects than in age-and weight-matched controls.Thus, it would appear that the risk for CHD in FCHL extends beyond insulin resistance and increases in IAF and also likely beyond the presence of small, dense LDL, which occurs in both. ApoB and/or the lipoprotein(s) in which apoB is transported appear to be the culprit. This raises...

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