Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia (FHBL) type 2 in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low LDL phenotype in carriers of ANGPTL3 mutations is unexplained.Objective: To determine whether a reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to study the whether PCSK9 is involved in determining low LDL levels in this condition.Design: We studied subjects from 19 families with ANGPTL3 mutations, and subjects with FHBL type 1 due to truncated apolipoprotein B (apoB) species.Results: Total cholesterol, HDL-c, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels, but only when this was below 25% of normal (<60 ng/ml); (ii) VLDL particle concentration strongly correlated with plasma ANGPTL3 when this was below 58% of normal; (iii) both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9, and higher levels of its furin-cleaved form; and (iv) LDL-bound PCSK9 is protected from cleavage by furin, and binds to the LDL receptor more strongly compared to apoB-free PCSK9.Conclusion: Our studies suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on threshold plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.
|Numero di pagine||9|
|Rivista||THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM|
|Stato di pubblicazione||Published - 2017|
All Science Journal Classification (ASJC) codes
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical