Abstract 18296: Investigation of Hepatic and Vascular Changes Associated with Familial Combined Hypolipidemia

Abstract

Background. Familial combined hypolipidemia (FHBL2, OMIM #605019), due to mutations in ANGPTL3 gene, is a rare low-cholesterol syndrome characterized by a profound reduction of pro-atherogenic, apoB-containing and anti-atherogenic, apoAI- containing lipoproteins. FHBL2 individuals show reduced hepatic production of very low density lipoprotein, a condition predisposing to fatty liver. However, the impact of FHBL2 on risk of atherosclerosis or hepatic steatosis is unknown.

Methods and Results. We assessed in 66 FHBL2 subjects carrying the ANGPTL3 S17X LOF mutation (7 homozygotes and 59 heterozygotes) and 126 age- and sex-matched controls the extent of preclinical atherosclerosis, by measuring carotid intima-media thickness (IMT) and flow-mediated dilatation (FMD), as well as the prevalence of hepatic steatosis by abdominal ultrasonography. Compared with controls, homozygous, but not heterozygous, FHBL2 carriers showed increased average and maximum IMT (P<0.01). Homozygous carriers also showed lower, although not significant, FMD. Compared to controls, ApoB-depleted sera from FHBL2 individuals had a reduced capacity to promote cell cholesterol efflux (4.9 ± 1.8 % vs. 8.5 ± 1.6 %; P<0.01). This was evident with ABCA1-, SR-BI- and ABCG1-mediated pathways and was related to the number of mutated alleles. No difference in the prevalence of hepatic steatosis was found between FHBL2 and controls.

Conclusions. Homozygous FHBL2 are at increased risk of developing early vascular atherosclerotic changes and that this might be related to the severely impaired HDL function in these subjects. FHBL2 subjects did not show increased risk of hepatic steatosis, thus supporting the notion that Angplt3 deficiency exerts its metabolic effects not impairing the secretion of TG by the liver.