Post-transcriptional Regulation of Low Density Lipoprotein Receptor Protein by Proprotein Convertase Subtilisin/Kexin Type 9a in Mouse Liver

• Published in: The Journal of biological chemistry Vol. 279; no. 48; pp. 50630 - 50638
• Main Authors: Park, Sahng Wook, Moon, Young-Ah, Horton, Jay D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.11.2004; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; CCAAT-Enhancer-Binding Proteins - metabolism; CHO Cells; Cricetinae; DNA-Binding Proteins - metabolism; Liver - metabolism; Mice; Mutation; Proprotein Convertase 9; Proprotein Convertases; Receptors, LDL - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Time Factors; Transcription Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M410077200

Lipid homeostasis is transcriptionally regulated by three DNA-binding proteins, designated sterol regulatory element-binding protein (SREBP)-1a, -1c, and -2. Oligonucleotide arrays hybridized with RNA made from livers of transgenic SREBP-1a, transgenic SREBP-2, and SREBP cleavage-activating protein knockout mice recently identified 33 genes regulated by SREBPs in liver, four of which had no known connection to lipid metabolism. One of the four genes was PCSK9, which encodes proprotein convertase subtilisin/kexin type 9a, a protein that belongs to the proteinase K subfamily of subtilases. Mutations in PCSK9 are associated with an autosomal dominant form of hypercholesterolemia. Here, we demonstrate that hepatic overexpression of either wild-type or mutant PCSK9 in mice results in hypercholesterolemia. The hypercholesterolemia is due to a post-transcriptional event causing a reduction in low density lipoprotein (LDL) receptor protein prior to the internalization and recycling of the receptor. Overexpression of PCSK9 in primary hepatocytes and in mice lacking the LDL receptor does not alter apolipoprotein B secretion. These data are consistent with PCSK9 affecting plasma LDL cholesterol levels by altering LDL receptor protein levels via a post-transcriptional mechanism.