Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.
The gene encoding the proprotein convertase subtilisin/kexin type 9 (PCSK9) is linked to familial hypercholesterolemia, as are those of the low-density lipoprotein receptor (LDLR) and apolipoprotein B. PCSK9 enhances LDLR degradation, resulting in low-density lipoprotein accumulation in plasma. To analyze the role of hepatic PCSK9, total and hepatocyte-specific knockout mice were generated. They exhibit 42% and 27% less circulating cholesterol, respectively, showing that liver PCSK9 was responsible for two thirds of the phenotype. We also demonstrated that, in liver, PCSK9 is exclusively expressed in hepatocytes, representing the main source of circulating PCSK9. The data suggest that local but not circulating PCSK9 regulates cholesterol levels. Although transgenic mice overexpressing high levels of liver and circulating PCSK9 led to the almost complete disappearance of the hepatic LDLR, they did not recapitulate the plasma cholesterol levels observed in LDLR-deficient mice. Single LDLR or double LDLR/PCSK9 knockout mice exhibited similar cholesterol profiles, indicating that PCSK9 regulates cholesterol homeostasis exclusively through the LDLR. Finally, the regenerating liver of PCSK9-deficient mice exhibited necrotic lesions, which were prevented by a high-cholesterol diet. However, lipid accumulation in hepatocytes of these mice was markedly reduced under both chow and high-cholesterol diets, revealing that PCSK9 deficiency confers resistance to liver steatosis.


CONCLUSIONS
Although PCSK9 is a target for controlling hypercholesterolemia, our data indicate that upon hepatic damage, patients lacking PCSK9 could be at risk.
Zaid
Ahmed
A
Laboratorie of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, affiliated to the University of Montreal, Montreal, Quebec, Canada.
Roubtsova
Anna
A
Essalmani
Rachid
R
Marcinkiewicz
Jadwiga
J
Chamberland
Ann
A
Hamelin
Josée
J
Tremblay
Michel
M
Jacques
Hélène
H
Jin
Weijun
W
Davignon
Jean
J
Seidah
Nabil G
NG
Prat
Annik
A
D000818:Animals; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D005234:Fatty Liver / Q000517:prevention & control; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism*; D007113:Immunity, Innate; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009336:Necrosis; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D014018:Tissue Distribution; D015854:Up-Regulation
D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases