Dataset Information

Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?

ABSTRACT: A genome-wide association study suggested that a R504H mutation in the proprotein convertase PC7 is associated with increased circulating levels of HDL and reduced triglycerides in black Africans. Our present results show that PC7 and PC7-R504H exhibit similar processing of transferrin receptor-1, proSortilin, and apolipoprotein-F. Plasma analyses revealed no change in the lipid profiles, insulin or glucose of wild type and PC7 KO mice. Thus, the R504H mutation does not modify the proteolytic activity of PC7. The mechanisms behind the implication of PC7 in the regulation of human HDL, triglycerides and in modifying the levels of atherogenic small dense LDL remain to be elucidated.

SUBMITTER: Guillemot J

PROVIDER: S-EPMC4208093 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?

Guillemot Johann J Essalmani Rachid R Hamelin Josée J Seidah Nabil G NG

FEBS open bio 20140902

A genome-wide association study suggested that a R504H mutation in the proprotein convertase PC7 is associated with increased circulating levels of HDL and reduced triglycerides in black Africans. Our present results show that PC7 and PC7-R504H exhibit similar processing of transferrin receptor-1, proSortilin, and apolipoprotein-F. Plasma analyses revealed no change in the lipid profiles, insulin or glucose of wild type and PC7 KO mice. Thus, the R504H mutation does not modify the proteolytic ac ...[more]

PMID: 25349778

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Project description:Alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid-lowering therapies are unclear. Every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. Low-density lipoprotein cholesterol (LDL-C), PCSK9, and alirocumab levels were assessed in subjects (LDL-C >130 mg/dL, n=24/group) after a 4-week run-in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL-C reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL-C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo. Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid-lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly. URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.

Dataset Information

Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?

Publications

Is there a link between proprotein convertase PC7 activity and human lipid homeostasis?

Similar Datasets

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