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Fig. 1 | Cardiovascular Diabetology

Fig. 1

From: Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

Fig. 1

PCSK9 in lipid metabolism. a (1) The canonical pathway: secreted PCSK9 can bind to the EGF-A domain of low-density lipoprotein receptor (LDLR) on the cell surface and be internalized with LDLRs in endocytic vesicles. The PCSK9–LDLR complex is then degraded in lysosomes. (2) Intracellular endogenous PCSK9-induced LDLR degradation: PCSK9 can bind to LDLR in the luminal secretory compartment and target LDLR to lysosomes in vesicles emanating from the trans-Golgi. (3) PCSK9-mediated very low-density lipoprotein receptor (VLDLR) degradation: the EGF-A domain of VLDLR is homologous to the EGF-A domain of LDLR. Extracellular PCSK9 interacts with VLDLR by binding with the EGF-A domain to form an endocytosed complex that is degraded in lysosomes. b The Beclin-1/ATG14L complex initiates the autophagy process that degrades apolipoprotein B (apoB). P62 shuttles proteins and organelles to autophagosomes for degradation. The conversion of LC3-I to LC3-II indicates active turnover of the autophagy process. PCSK9 interacts with apoB, resulting in the inhibition of the degradation pathway of apoB via this autophagic mechanism. Thus, the secretion of apoB100, as the particles VLDL, LDL, and Lipoprotein(a) (Lp(a)), into circulation is increased. PCSK9 antibodies increase the expression of LDLR, which can bind with exogenous Lp(a). Thus, the Lp(a)/LDLR complex is internalized and undergoes the lysosome degradation pathway

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