Background and Aims

Individuals with loss-of-function (LOF) mutations in ANGPTL3 gene express a unique lipid phenotype characterized by a comprehensive reduction of ApoB and Apo-AI -containing lipoproteins (so called Familial Combined Hypolipidemia or FHBL2). ANGPTL3 modulates lipoprotein metabolism by suppressing LPL and EL activity. The effect of lack of ANGTPL3 on HDL is poorly explored.

In this work, we investigated the structure and function of HDL particles in an Italian cohort of FHBL2 carriers.

Methods

Fifteen carriers of ANGPTL3 LOF mutations (5 homozygotes and 10 heterozygotes) and 10 non-affected family members (Controls) were considered. HDLs were purified by sequential ultracentrifugation from serum and analyzed for subclasses composition. Furthermore, the ability of isolated HDL to modulate the release of nitric oxide (NO) and the expression of adhesion molecules was evaluated in cultured endothelial cells.

Results

ANGPTL3 deficiency alters HDL subclass distribution. Compared with Controls, Homozygotes shown a reduced content of large HDL particles and an increased content of small particles with no alteration in HDL2 and HDL3 size. The plasma content of preβ-HDL, drastically reduced in homozygous carriers, was positively correlated with the plasma levels of ANGPTL3. Moreover, as compared with control, the capacity of HDL isolated from homozygotes to promote NO production as well as to suppress the expression of the adhesion molecules in endothelial cells were preserved.

Conclusions

These results indicated that the reduction of HDL-C level and the alteration of HDL subclass distribution observed in subjects with genetically determined ANGPTL3 deficiency does not hamper the vaso-protective and the anti-inflammatory properties of this lipoprotein fraction