Infodating org

31 Jan

It is therefore possible that PCSK9 may require another cell-specific protein to exert its effect on the LDLR.

Thus, the exact mechanism by which PCSK9 degrades the LDLR remains to be determined.

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gene have been associated with both hypocholesterolemia and hypercholesterolemia through ‘loss-of-function’ and ‘gain-of-function’ mechanisms, respectively.

These mutations are referred to as ‘loss-of-function’ mutations, but as of yet, no studies of how these mutations affect the LDLR have been performed.

infodating org-28infodating org-75

For the D374Y gain-of-function mutation, no significant reduction in the number of cell surface LDLR (18,21) or internalization of LDL (21) has been found by studies of EBV-transformed lymphocytes from D374Y heterozygotes.

As the reduced number of LDLR, by PCSK9, is not accompanied by changes in LDLR m RNA levels (6,7), PCSK9 is apparently involved in the post-transcriptional regulation of the LDLR.

Degradation of the LDLR by PCSK9 is dependent on maintained catalytic activity of PCSK9 (7,9) and appears to take place in a post-Golgi compartment or at the cell surface (7,9,10). Overexpression of reduces the number of LDLR in liver and kidney cells (7,8), but not in fibroblasts, the Huh7 human hepatoma cell line or in chinese hamster ovary cells (7).

We have studied the effect of the four loss-of-function mutations R46L, G106R, N157K and R237W and the two gain-of-function mutations S127R and D374Y on the autocatalytic activity of , as well as on the amount of the cell surface LDLR and internalization of LDL in transiently transfected Hep G2 cells.

The two groups of mutations did not differ with respect to autocatalytic activity of , but they did differ with respect to the amount of cell surface LDLR and internalization of LDL.