In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia

Overproduction of very low density lipoprotein (VLDL) is the major characte ristic of subjects with familial combined hyperlipidemia (FCHL). As enhance d 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 me tabolism in response to a 24-h oral fat loading test (50 g/m(2)) in 7 FCHL subjects and 7 matched control subjects, The response to the meal was subdi vided into a postprandial (up to 8 h after ingestion of the meal) and posta bsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic ac tivities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAU C) 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 f our times higher in FCHL patients,As ketogenesis occurs predominantly in he patocytes, these findings suggest that during the postprandial period in FC HL an increased flux of FFA to the liver occurs, possibly because of inadeq uate incorporation of FFA into triglycerides (TGs) in adipocytes, In the po stabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These re sults 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-media ted inhibition of HSL, as both FCHL subjects and control subjects had simil ar postabsorptive insulin concentrations, which were below fasting concentr ations. This study provides in vivo evidence of impaired metabolism of post prandial FFA in FCHL, which may explain in part the hepatic VLDL overproduc tion characteristic of FCHL subjects.