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Abstract-Very low density lipoprotein overproduction is the major metabolic characteristic in familial combined hyperlipidemia (FCHL). Peripheral handling of free fatty acids (FFAs) in vitro may be impaired in FCHL by decreased action of acylation-stimulating protein (ASP), which is identical to the immunologically inactive complement component 3a (C3adesArg

Objective-An increased hepatic flow of free fatty acids (FFAs) is associated with impaired peripheral FFA trapping by malfunctioning of the complement component 3 (C3)/acylation-stimulating protein system and overproduction of VLDL in familial combined hyperlipidemia (FCHL). Postprandial ketone bodies reflect FFA oxidation in the liver, but the postprandial changes in male and female patients separately have not been determined yet. Gender differences in postprandial ketone bodies and C3 changes were investigated in normolipidemic patients and patients with untreated FCHL. Methods and Results-Thirty-two normolipidemic patients (16 female and 16 male) and 19 patients with untreated normolipidemia (9 female and 10 male) underwent an oral fat-loading test. Total and incremental areas under the curves (AUC and dAUC, respectively) after the oral fat load were calculated. Triglyceride AUC was similar between genders in each group. Normolipidemic female subjects showed a higher levels of dAUC-hydroxybutyric acid than male subjects (1.37Ϯ0.49 and 0.98Ϯ0.43 mmol · h/L). In FCHL, a similar trend was observed in female (1.92Ϯ0.38) compared with male (1.55Ϯ0.87) subjects. In contrast to normolipidemia, FCHL did not show a postprandial increase in C3, although C3 was higher in FCHL. Conclusions-Women

The diagnosis is based on clinical criteria such as the presence of "multiple-type hyperlipidemia," increased plasma apolipoprotein B (apoB), and a positive family history of premature coronary heart disease (CHD) (1-10). Abdominal obesity and increased body mass index (BMI) have been identified as independent factors for the development of hyperlipidemia and CHD in FCHL (4,8,(10)(11)(12). Associations with the complement system have also been reported (13,14). The genetic basis of FCHL has not been elucidated, although several groups have provided evidence suggesting that different genes are involved in the pathogenesis of this disorder (15-23).Impaired FFA metabolism in the postprandial as well as in the postabsorptive period is closely related to the expression of the FCHL phenotype (24-28). FCHL patients have increased postprandial FFA concentrations, compared with healthy controls (24,26,27). Increased postprandial FFA concentrations result in an increased postprandial hepatic FFA flux, which could explain in part the well-known VLDL overproduction in FCHL (26). More recently, an impaired postprandial complement component 3 (C3) response has been associated with the disturbed postprandial FFA handling (27).In vitro and in vivo experiments have demonstrated that the uptake of FFA by peripheral cells is stimulated by acylation-stimulating protein (ASP) (29, 30), which is one of the immunologically inactive cleavage products of C3 (30). Different studies in FCHL and non-FCHL subjects have shown a strong correlation between fasting C3 concentrations and fasting lipid parameters, especially plasma triglycerides (TGs) (13,14,27,31,32). Furthermore, C3 is a powerful indicator for the risk of myocardial infarction in men (32), and recently, it has been shown that C3 depositions are found predominantly in ruptured atherosclerotic plaques in humans (33), suggesting a pathogenetic involvement in the process of atherosclerosis and acute coronary syndromes. Moreover, both fasting and post-