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

Abstract

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.