PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice.

Journal of Lipid Research
Anna RoubtsovaAnnik Prat

Abstract

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...Continue Reading

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Citations

Jan 18, 2017·Pediatric Diabetes·Amy E LevensonSudha B Biddinger
Nov 9, 2018·Journal of Molecular Endocrinology·Quinn DufurrenaRegina Kuliawat
Jan 30, 2016·Endocrinology·Amy E LevensonSudha B Biddinger
Nov 2, 2019·Biomolecules·Lucas Pires GuarnierArquimedes Gasparotto Junior
Jan 13, 2019·International Journal of Molecular Sciences·Marica BordicchiaRiccardo Sarzani
Dec 18, 2020·Clinica Chimica Acta; International Journal of Clinical Chemistry·Die HuDaoquan Peng
Jan 1, 2021·Endocrine Reviews·Manita Shakya, Iris Lindberg
Mar 30, 2021·Frontiers in Aging Neuroscience·Paola G SimeoneFrancesca Santilli
May 17, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Marie-Line PeyotAnnik Prat
Jul 30, 2021·European Heart Journal·Kevin ChemelloGilles Lambert
Oct 10, 2021·Endocrine Reviews·Nabil G Seidah, Annik Prat

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