In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that plays a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol levels. PCSK9 binding to the LDL receptor (LDLR) leads to receptor-mediated endocytosis and lysosomal degradation of LDLR. Prior studies have shown that PCSK9 increases production of triglyceride-rich apoB-lipoproteins via up-regulation of lipogenic genes, and that PCSK9 inhibition reduces plasma triglyceride levels. However, the effect of PCSK9 inhibition on hepatic lipogenic genes expression remain unclear. Using a human hepatocellular carcinoma cell line (HepG2) we show that overexpression of PCSK9 upregulated the expression of several lipogenic genes, including a 1.5-fold increase in ATP citrate lyase (ACLY), a 1.2-fold increase in Fatty Acid Synthase (FAS), a 1.2-fold increase in HMG-CoA-reductase, and a 1.8-fold increase in microsomal triglyceride transfer protein (MTTP), when compared with untransfected HepG2 cells. Overexpression of a gain-of-function mutant of PCSK9 (PCSK9-D374Y) had stronger effects in the same direction: a 2.3-fold increase in ACLY, a 1.8-fold increase in FAS, a 1.6-fold increase in HMG-CoA-reductase, and a 2.1-fold increase in MTTP. In HepG2 cells overexpressing either normal PCSK9 or PCSK9-D374Y, inhibition of PCSK9 function using a monoclonal antibody blocked PCSK9-mediated degradation of LDLR, and reduced expression of SREBP-dependent genes (ACLY, FAS and HMG-CoA-reductase) to levels of untransfected HepG2 cells. Interestingly, while inhibition of PCSK9 function via monoclonal antibody did not affect MTTP gene expression in these cells, inhibition of PCSK9 production via RNA interference reduced MTTP gene expression by 66%. We conclude that inhibition of PCSK9 production decreases MTTP gene expression, whereas blockade of PCSK9 function (and cellular re-entry) only decreases SREBP-dependent genes expression, but does not affect MTTP gene expression. This study shows that while PCSK9 exerts an influence on genes related to both lipogenesis and lipoprotein assembly, any inhibition of PCSK9 controls SREPB-dependent genes but only inhibiting PCSK9 production controls MTTP gene expression.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/atvb.38.suppl_1.033
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
1494427-3
