PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice.
Proprotein convertase subtilisin kexin type 9 (PCSK9), the last member of the family of Proprotein Convertases related to Subtilisin and Kexin, regulates LDL-cholesterol by promoting the endosomal/lysosomal degradation of the LDL receptor (LDLR). Herein, we show that the LDLR cell surface levels dramatically increase in the liver and pancreatic islets of PCSK9 KO male but not female mice. In contrast, in KO female mice, the LDLR is more abundant at the cell surface enterocytes, as is the VLDL receptor (VLDLR) at the cell surface of adipocytes. Ovariectomy of KO female mice led to a typical KO male pattern, whereas 17β-estradiol (E2) treatment restored the female pattern without concomitant changes in LDLR adaptor protein 1 (also known as ARH), disabled-2, or inducible degrader of the LDLR expression levels. We also show that this E2-mediated regulation, which is observed only in the absence of PCSK9, is abolished upon feeding the mice a high-cholesterol diet. The latter dramatically represses PCSK9 expression and leads to high surface levels of the LDLR in the hepatocytes of all sexes and genotypes. In conclusion, the absence of PCSK9 results in a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR, which is determined by E2 levels.
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Anna
A
Roubtsova
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Ann
A
Chamberland
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Jadwiga
J
Marcinkiewicz
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Rachid
R
Essalmani
Department of Medicine, McGill University Hospital Research Institute, Montreal, Quebec, Canada.
Ali
A
Fazel
Department of Medicine, McGill University Hospital Research Institute, Montreal, Quebec, Canada.
John J
JJ
Bergeron
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Nabil G
NG
Seidah
Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), Montreal, Quebec, Canada.
Annik
A
Prat
D050154:Adiposity; D000818:Animals; D004958:Estradiol / Q000502:physiology; D005260:Female; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D012727:Sex Characteristics
D012333:RNA, Messenger; D011973:Receptors, LDL; C036053:VLDL receptor; D004958:Estradiol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
cholesterol; estrogen; ldl/metabolism; lipoproteins/receptors; liver