Abstract
The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. We studied 7 homozygous (undetectable circulating ANGPTL3 levels) and 31 heterozygous (50% of circulating ANGPTL3 levels) subjects with familial combined hypolipidemia (FHBL2) due to inactivating ANGPTL3 mutations in comparison with 35 controls. All subjects were evaluated at fasting and during 6 h after a high fat meal. Postprandial lipid and lipoprotein changes were quantified by calculating the areas under the curve (AUCs) using the 6 h concentration data. Plasma changes of β-hydroxybutyric acid (β-HBA) were measured as marker of hepatic oxidation of fatty acids. Compared with controls, homozygotes showed lower incremental AUCs (iAUCs) of total TG (-69%, P < 0.001), TG-rich lipoproteins (-90%, P < 0.001), apoB-48 (-78%, P = 0.032), and larger absolute increase of FFA (128%, P < 00.1). Also, heterozygotes displayed attenuated postprandial lipemia, but the difference was significant only for the iAUC of apoB-48 (-28%; P < 0.05). During the postprandial period, homozygotes, but not heterozygotes, showed a lower increase of β-HBA. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietary-derived fatty acids into the liver. These results add information on mechanisms underlying hypolipidemia in FHBL2.
Highlights
The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans
We have examined the effect of ANGPTL3 deficiency on postprandial lipid metabolism by investigating familial combined hypolipidemia (FHBL2) subjects carrying an inactivating mutation in the ANGPTL3 gene
Our data demonstrate that, compared with controls, postprandial elevation of TG-rich lipoprotein (TRL) was markedly attenuated in homozygous FHBL2 subjects, whereas it was modestly changed in heterozygotes
Summary
The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietaryderived fatty acids into the liver These results add information on mechanisms underlying hypolipidemia in FHBL2.—Minicocci, I., A. Animals overexpressing ANGPTL3 and Abbreviations: ANGPTL3, angiopoietin-like protein 3; ANGPTL4, angiopoietin-like protein 4; AUC, area under the curve; CETP, cholesterol ester transfer protein; FABP4, fatty acid binding protein-4; FHBL2, familial combined hypolipidemia; FM, fat mass; FFM, free fat mass; FPLC, fastperformance liquid chromatography; HDL-C, HDL cholesterol; HBA, -hydroxybutyric acid; iAUC, incremental area under the curve; LDL-C, LDL cholesterol; LOF, loss-of-function; MET, metabolic equivalent; OFTT, oral fat tolerance test; PLTP, phospholipid transfer protein; PON1, paraoxonase 1; REE, resting energy expenditure; RP, retinyl palmitate; TRL, TG-rich lipoprotein. ANGPTL4 show lower LPL activities and hypertriglyceridemia [12], while those lacking ANGPTL3 have reduced levels of TGs and FFAs and increased LPL activity [10, 12]
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