Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans.
OBJECTIVE
To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes.


RESULTS
We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid-binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels.


CONCLUSIONS
Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.
Persson
Lena
L
Department of Endocrinology, Center for Biosciences and Nutrition, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Cao
Guoqing
G
Ståhle
Lars
L
Sjöberg
Beatrice G
BG
Troutt
Jason S
JS
Konrad
Robert J
RJ
Gälman
Cecilia
C
Wallén
Håkan
H
Eriksson
Mats
M
Hafström
Ingiäld
I
Lind
Suzanne
S
Dahlin
Maria
M
Amark
Per
P
Angelin
Bo
B
Rudling
Mats
M
D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002792:Cholestyramine Resin / Q000008:administration & dosage; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D055423:Diet, Ketogenic; D015536:Down-Regulation; D002149:Energy Intake; D005215:Fasting / Q000097:blood*; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D019382:Human Growth Hormone / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011758:Pyrroles / Q000008:administration & dosage; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000097:blood*; D013548:Sweden
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011973:Receptors, LDL; D002792:Cholestyramine Resin; D019382:Human Growth Hormone; C001521:lathosterol; D002784:Cholesterol; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases