RGD Reference Report - Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. - Rat Genome Database

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Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c.

Authors: Costet, P  Cariou, B  Lambert, G  Lalanne, F  Lardeux, B  Jarnoux, AL  Grefhorst, A  Staels, B  Krempf, M 
Citation: Costet P, etal., J Biol Chem. 2006 Mar 10;281(10):6211-8. Epub 2006 Jan 6.
RGD ID: 8553473
Pubmed: PMID:16407292   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M508582200   (Journal Full-text)

Familial autosomal dominant hypercholesterolemia is associated with high risk for cardiovascular accidents and is related to mutations in the low density lipoprotein receptor or its ligand apolipoprotein B (apoB). Mutations in a third gene, proprotein convertase subtilisin kexin 9 (PCSK9), were recently associated to this disease. PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory element-binding protein (SREBP). Here we investigated the regulation of PCSK9 gene expression during nutritional changes. We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. In contrast PCSK9 expression was restored upon high carbohydrate refeeding. PCSK9 mRNA increased by 4-5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. Moreover, insulin up-regulated hepatic PCSK9 expression in vivo during a hyperinsulinemic-euglycemic clamp in mice. Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression. Liver X receptor agonist T0901317 also regulated PCSK9 expression via this same pathway (a 2-fold increase in PCSK9 mRNA of primary hepatocytes cultured for 24 h in presence of 1 microm T0901317). As our last investigation, we isolated PCSK9 proximal promoter and verified the functionality of a SREBP-1c responsive element located from 335 bp to 355 bp upstream of the ATG. Together, these results show that PCSK9 expression is regulated by nutritional status and insulinemia.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to insulin stimulus involved_inIDA 8553473PMID:16407292HGNC-UCL 
cellular response to starvation involved_inIDA 8553473; 8553473PMID:16407292HGNC-UCL 
positive regulation of transcription by RNA polymerase II involved_inIDA 8553473PMID:16407292NTNU_SB 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Pcsk9  (proprotein convertase subtilisin/kexin type 9)
Srebf1  (sterol regulatory element binding transcription factor 1)


Additional Information