Page 6 - SHJ VOL 5, NO 1
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SHJ Vol 5, No 1                                M Ibrahim, Putting PCSK9 Inhibitors into practice
            capacity to synthesize cholesterol. However, the      and,   consequently,    increased    risk   of
            majority  of  circulating  LDL  cholesterol  is       cardiovascular disease (15). The protein, called
            synthesized  in  the  liver,  by  HMG-CoA             proprotein  convertase  subtilisin/kexin  type  9
            reductase and the principal means of removal of       (PCSK9), had been discovered earlier that year
            LDL  cholesterol  from  the  circulation  is  via  a   by Canadian researchers (16).
            family  of  hepatic  LDL  receptors.  Current         Inhibition of this protein is a novel therapeutic
            therapies  are  targeted  at  reducing  the  rate  of   concept  based  on  reduction  of  plasma  LDL
            cholesterol  biosynthesis  (the  main  effect  of     cholesterol through increased hepatic clearance.
            statins)  or  reducing  the  rate  of  absorption  of   The binding of the PCSK9 protein to the LDL
            cholesterol into the circulation (ezetimibe, bile     receptor  increases  the  probability  of  the  LDL
            acid  sequestrants  or  plant  sterols/stanols)       receptor  then  being  diverted  to  a  lysosome,
            derived from food and/or from bile.                   where it is degraded, rather than being recycled
                                                                  to the cell membrane as usual (17).
            The LDL receptor on the surface of liver cells is
            an  essential  component  of  the  machinery  for     A number of mutations and polymorphisms of
            regulating  levels  of  LDL  cholesterol.  Once  an   the  PCSK9  gene  have  been  identified,  which
            LDL particle binds to this receptor, it is rapidly    support its importance in the regulation of LDL
            bound  at  a  coated  pit  and  taken  up  within  an   cholesterol.  These  include  ―loss  of  function‖
            intracellular  endosome,  and  then  catabolized      and  ―gain  of  function‖  mutations  that  reduce
            within  a  lysosome,  where  the  LDL  particle  is   and  increase,  respectively,  the  activity  of
            dissociated from the LDL receptor at acid PH.         PCSK9 (Table1) (18).
            The  lipid  and  protein  content  of  the  LDL       Common loss-of-function mutations in PCSK9
            particle  is  then  degraded.  The  LDL  receptor     in  humans  are  associated  with  lower  LDL
            protein  then  recycles  back  to  the  cell  surface.   cholesterol and a reduced frequency of adverse
            Most    (90–95%)     patients   with   familial       cardiovascular  events,  compared  with  subjects
            hypercholesterolemia  have  mutations  in  the        with wild-type
            LDLR gene that result in reduced or abolished         PCSK9. For example:
            LDL receptor function or a reduced number of
            LDL  receptor  protein  molecules  on  the  cell      • 2.6% of Black subjects in the Atherosclerosis
            surface.         Heterozygous          familial       Risk in Communities (ARIC) study in the USA
            hypercholesterolemia is the most common form          had  a  nonsense  (loss  of  function)  mutation  in
            of the disease, with potential for loss of up to      the  PCSK9  gene  (0.8%  for  the  Y142X  allele
            50% of LDL receptor activity.                         and  1.8%  for  the  C679X  allele).  Their  mean
                                                                  LDL  cholesterol  was  reduced  by  28%
            The discovery                                         (p=0.008)  vs.  non-carriers  of  these  mutations,
            In  2003,  French  researchers  identified  high      and this was associated with an 88% lower risk
            levels  of  a  protein  in  a  family  with  familial   of  coronary  heart  disease  (age-and  gender-
            hypercholesterolemia, an inherited disease that       adjusted hazard ratio [HR] 0.11 [95%CI 0.02 to
            leads  to  dangerously  high  blood  cholesterol      0.81]; p=0.03) (19).

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