Membrane Type 1-Matrix Metalloproteinase Mediates Degradation of the Low-density Lipoprotein Receptor Family Members

• Author / Creator

  Zhang, Ziyang

• The low-density lipoprotein receptor (LDLR) family includes 13 transmembrane protein members sharing a conserved structure and common repeats. Their importance has been shown in a variety of physiological and pathophysiological events including lipid metabolism, nervous system development and maintenance, bone homeostasis and cancer progression. Cell surface LDLR family members are regulated by metalloproteinases-mediated ectodomain shedding. Membrane type 1-matrix metalloproteinase (MT1-MMP) is a key player in extracellular matrix remodelling and has been reported to cleave LDLR, low-density lipoprotein receptor-related protein 1 (LRP1) and LRP4. To study the effect of MT1-MMP on other LDLR family members, MT1-MMP and LDLR family members were co-overexpressed by transient transfection in the human hepatoma-derived Huh7 cell line. Herein, we found that MT1-MMP is able to mediate the shedding of all screened LDLR family members, including LRP3, LRP4, LRP5, LRP6, LRP8, LRP10, LRP11, and LRP12. The proteolytic activity of MT1-MMP is required for the shedding except for LRP10. In the cases of LRP3 and LRP11, the C-terminal fragments of the receptors were detected in cells after the MT1-MMP-mediated cleavage. The biological importance of MT1-MMP-mediated shedding of LDLR family members is unknown, which requires further investigation.
  In addition, we investigated the combinative effect of targeting MT1-MMP with statin treatment in raising LDLR levels. Statin monotherapy can only achieve a ~50% cholesterol-lowering effect and is accompanied by dose-dependent adverse effects such as increased onset risk of type 2 diabetes. Thus, combination therapy with statin and a nonstatin cholesterol-lowering medication is recommended to enhance cholesterol-lowering outcomes and reduce statin-associated adverse effects. In HepG2 cells, MT1-MMP knockdown can additionally increase LDLR expression levels in the presence of statin treatment. We also studied hepatic MT1-MMP depletion combined with statin treatment in mice.

• Subjects / Keywords

  • MT1-MMP
  • LDLR family

• Graduation date

  Spring 2024

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-kqc7-s307

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.