TY  - CHAP
M1  - Book, Section
TI  - Type III Hyperlipoproteinemia (Dysbetalipoproteinemia): The Role of Apolipoprotein E in Normal and Abnormal Lipoprotein Metabolism
A1  - Mahley, Robert W.
A1  - Rall, Stanley C.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Patients  with  type  III  hyperlipoproteinemia  have  elevated  concentrations  of  both  plasma  cholesterol  and  triglyceride.  A  biochemical  characteristic  of  the  disorder  is  the  occurrence  of  β-migrating  VLDL  (β-VLDL),  which  are  cholesterol-enriched  remnants  of  both  intestinal  chylomicrons  and  hepatic  VLDL.  The  β-VLDL  are  enriched  in  a  variant  form  of  apo  E,  which,  in  type  III  hyperlipoproteinemic  subjects,  is  dysfunctional.Clinical  features  of  the  disorder  are  varied.  Many  type  III  subjects  have  cutaneous  xanthomas,  particularly  tuberoeruptive  or  tuberous  xanthomas  and  xanthomas  of  the  palmar  creases  (xanthoma  striata  palmaris);  the  latter  have  not  been  identified  in  any  other  disorder.  These  patients  have  a  high  incidence  of  premature  coronary  and  (especially)  peripheral  atherosclerosis.  In  the  most  common  form  of  the  disease,  overt  hyperlipidemia  is  only  rarely  manifested  before  adulthood.  Type  III  subjects  frequently  have  other  disorders  that  exacerbate  the  hyperlipoproteinemia.Apolipoprotein  E  is  a  polymorphic  protein  that  results  from  the  existence  of  multiple  alleles  at  a  single  gene  locus  and  from  varying  posttranslational  sialylation.  The  genetically  determined  polymorphism  of  apo  E  has  a  significant  impact  on  normal  variations  in  lipid,  lipoprotein,  and  apolipoprotein  levels  in  the  human  population.  The  primary  molecular  defect  in  most  patients  with  type  III  hyperlipoproteinemia  is  the  presence  of  a  mutant  form  of  apo  E  (apo  E-2)  that  differs  from  normal  apo  E  (apo  E-3)  by  only  a  single  amino  acid  substitution  (cysteine  for  arginine  at  residue  158).  The  apo  E-2  variant  binds  poorly  to  low-density  lipoprotein  receptors  and  is  associated  with  a  recessive  mode  of  inheritance  of  type  III  hyperlipoproteinemia.  Other  rare  forms  of  mutant  apo  E  causing  type  III  hyperlipoproteinemia  appear  to  be  associated  with  dominant  inheritance.The  normal  catabolism  of  remnant  lipoprotein  particles,  which  is  directed  by  apo  E,  is  altered  in  type  III  hyperlipoproteinemia.  The  presence  of  the  defective  apo  E  results  in  the  accumulation  of  chylomicron  and  VLDL  remnants  (β-VLDL)  in  plasma.  These  particles  in  turn  have  a  propensity  for  uptake  by  macrophages  in  peripheral  tissues.  As  a  result  of  massive  cholesterol  deposition,  these  macrophages  become  foam  cells,  which  may  be  the  progenitors  of  cholesterol-laden  cells  in  the  atherosclerotic  lesion.In  the  recessive  form  of  the  disorder,  the  development  of  overt  hyperlipidemia  requires  the  inheritance  of  two  alleles  for  the  mutant  apo  E  [E-2(Arg  158  →  Cys)].  The  occurrence  of  the  defective  alleles  is  necessary  but  not  usually  sufficient  to  induce  the  type  III  hyperlipoproteinemia.  Most  E-2/2  subjects  are  either  normolipidemic  or  even  hypocholesterolemic.  Thus,  the  development  of  the  recessive  form  of  the  overt  hyperlipidemia  involves  other  genetic,  hormonal,  or  environmental  influences  that,  in  combination  with  the  defective  receptor  binding  of  apo  E,  precipitate  the  development  of  the  hypertriglyceridemia  and  hypercholesterolemia.  The  secondary  factors  include  hypothyroidism,  low-estrogen  conditions,  obesity,  diabetes,  and  age.In  the  dominant  form  of  the  disorder,  subjects  possessing  a  single  allele  for  one  of  the  rare  variants  of  apo  E  have  the  overt  hyperlipidemia,  presumably  from  birth.  Secondary  genetic,  hormonal,  or  environmental  factors  usually  are  not  required  to  precipitate  the  accumulation  of  remnant  lipoproteins  in  the  plasma,  but  secondary  factors  can  sometimes  modulate  the  severity  of  the  disorder.Diagnosis  of  type  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181449868
ER  -