Abstract
Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). As enhanced free fatty acid (FFA) flux to the liver may be one of the determinants of VLDL overproduction, we studied FFA changes and products of hepatic FFA metabolism in response to a 24-h oral fat loading test (50 g/m2) in 7 FCHL subjects and 7 matched control subjects. The response to the meal was subdivided into a postprandial (up to 8 h after ingestion of the meal) and postabsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic activities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAUC) were higher in FCHL subjects than in control subjects (6.05 ± 0.45 vs. 3.43 ± 0.46 and 2.60 ± 0.49 vs. 0.96 ± 0.31 mmol·h/L, respectively; P < 0.01 for each). The postprandial increase in ketone bodies was almost four times higher in FCHL patients. As ketogenesis occurs predominantly in hepatocytes, these findings suggest that during the postprandial period in FCHL an increased flux of FFA to the liver occurs, possibly because of inadequate incorporation of FFA into triglycerides (TGs) in adipocytes. In the postabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. The decrease in postabsorptive FFA and ketone bodies in FCHL patients could not be explained by insulin-mediated inhibition of HSL, as both FCHL subjects and control subjects had similar postabsorptive insulin concentrations, which were below fasting concentrations.This study provides in vivo evidence of impaired metabolism of postprandial FFA in FCHL, which may explain in part the hepatic VLDL overproduction characteristic of FCHL subjects.
Highlights
Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL)
In the present study in vivo evidence of disturbed free fatty acid (FFA) metabolism in FCHL has been provided, which is in agreement with several in vitro studies
It has been suggested that in FCHL there is a defect in the adipose tissue metabolism of FFA and part of the features mentioned in FCHL could be explained by these defects [19]
Summary
Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. Maslowska, and Sniderman [20] have shown in vitro that the fatty acid uptake by peripheral cells and incorporation into triglycerides in patients with hyperapobetalipoproteinemia (hyperapoB) is impaired, because of diminished activity and binding of Abbreviations: ACA, aceto-acetate; ASP, acylation stimulating protein; AUC, area under the curve; dAUC, delta (incremental) area under the curve; CHD, coronary heart disease; ELISA, enzyme-linked immunosorbent assay; FCHL, familial combined hyperlipidemia; FFA, free fatty acid; HL, hepatic lipase; HDL-C, high density lipoprotein-cholesterol; HSL, hormone-sensitive lipase; HBA, hydroxybutyric acid; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very low density lipoprotein.
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