Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is predominantly expressed in liver and regulates cholesterol metabolism by down regulating liver LDL receptor (LDLR) proteins. Here we report transgenic overexpression of human PCSK9 in kidney increased plasma levels of PCSK9 and subsequently led to a dramatic reduction in liver LDLR proteins. The regulation of LDLR by PCSK9 displayed tissue specificity, with liver being the most responsive tissue. Even though the PCSK9 transgene was highly expressed in kidney, LDLR proteins were suppressed to a lower extent in this tissue than in liver. Adrenal LDLR proteins were not regulated by elevated plasma PCSK9. hPCSK9 transgene expression and subsequent reduction of liver LDLR led to increases in plasma total cholesterol, LDL cholesterol, and ApoB, which were further increased by a high-fat, high-cholesterol diet. We also observed that the size distribution of hPCSK9 in transgenic mouse plasma was heterogeneous. In chow-fed mice, the majority of PCSK9 proteins were in free forms; however, feeding a high-fat, high-cholesterol diet resulted in a shift of hPCSK9 distribution toward larger complexes. PCSK9 distribution in human plasma also exhibited heterogeneity and individual variability in the percentage of PCSK9 in free form and in large complexes. We provide strong evidence to support that human PCSK9 proteins secreted from extrahepatic tissue are able to promote LDLR degradation in liver and increase plasma LDL. Our data also suggest that LDLR protein regulation by PCSK9 has tissue specificity, with liver being the most responsive tissue.
Luo
Yi
Y
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton/New London Laboratories, Groton, CT 06340, USA. Yi.Luo@pfi zer.com
Warren
Laurie
L
Xia
Donghui
D
Jensen
Heather
H
Sand
Thomas
T
Petras
Stephen
S
Qin
Wenning
W
Miller
Kenneth S
KS
Hawkins
Julie
J
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D002784:Cholesterol / Q000032:analysis / Q000097:blood; D002791:Cholesterol, Dietary / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014280:Triglycerides / Q000032:analysis
D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases