2. Academic Validation
  3. PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

  • Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Dec;1867(12):159217. doi: 10.1016/j.bbalip.2022.159217.
Anna Roubtsova 1,  Damien Garçon 1,  Sandrine Lacoste 2,  Ann Chamberland 1,  Jadwiga Marcinkiewicz 1,  Raphaël Métivier 3,  Thibaud Sotin 4,  Martine Paquette 1,  Sophie Bernard 1,  Bertrand Cariou 5,  Cédric Le May 5,  Marlys L Koschinsky 6,  Nabil G Seidah 1,  Annik Prat 7
Affiliations

Affiliations

  • 1 Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada.
  • 2 Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada; S.L. present address: Centre de recherche de l'hôpital Maisonneuve Rosemont, Montreal, QC, Canada.
  • 3 Equipe SP@RTE, UMR 6290 CNRS, Université de Rennes 1, Rennes, France.
  • 4 Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada; Nantes Université, CHU Nantes, CNRS, INSERM, l'Institut du thorax, F-44000 Nantes, France.
  • 5 Nantes Université, CHU Nantes, CNRS, INSERM, l'Institut du thorax, F-44000 Nantes, France.
  • 6 Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
  • 7 Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada. Electronic address: Annik.Prat@ircm.qc.ca.
PMID: 35985474 DOI: 10.1016/j.bbalip.2022.159217
Abstract

PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI-8 raises by 80 % the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic Cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high Cholesterol feeding, or by E2 known to stimulate Cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver Cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain Cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80 % lower circulating LDL.

Keywords

Cholesterogenesis; ERalpha; Estrogen; Hepatocyte proliferation; Soluble LDLR.

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