RT Book, Section
A1 Tall, Alan R.
A1 Breslow, Jan L.
A1 Rubin, Edward M.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181450374
T1 Genetic Disorders Affecting Plasma High-Density Lipoproteins
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181450374
RD 2024/04/16
AB Plasma  high-density  lipoproteins  (HDL)  consist  of  about  50  percent  protein  and  50  percent  lipids.  The  principal  apolipoproteins  of  HDL,  apo  A-I  and  apo  A-II,  are  synthesized  in  the  liver  (apo  A-I  and  apo  A-II)  or  small  intestine  (apo  A-I),  secreted  as  components  of  triglyceride  (TG)-rich  lipoproteins  (TRL),  and  then  transferred  into  HDL  during  lipolysis,  along  with  phospholipid  and  cholesterol.  Alternatively,  they  may  be  secreted  as  free  apoproteins,  then  acquire  lipids  by  interaction  with  the  cellular  ATP  binding  cassette  transporter,  ABC1.  The  plasma  cholesterol-esterifying  enzyme  lecithin:  cholesterol  acyltransferase  (LCAT)  circulates  bound  to  HDL  and  uses  free  cholesterol  and  phospholipids  as  substrates  in  the  generation  of  cholesteryl  esters  (CE).  HDL  also  contains  a  phospholipid  transfer  protein  (PLTP)  and  a  cholesteryl  ester  transfer  protein  (CETP),  which  mediate  the  transfer  of  phospholipid  and  cholesterol  into  HDL  and  the  removal  of  cholesteryl  esters  from  HDL,  respectively.  CETP  mediates  a  hetero-exchange  of  HDL  CE  for  TG  of  TRL,  and  the  HDL  TG  is  subsequently  hydrolyzed  by  hepatic  lipase  (HL).  The  coordinate  activities  of  PLTP,  CETP,  LCAT,  and  HL  promote  the  formation  and  turnover  of  HDL  CE,  which  is  a  central  event  in  the  transport  of  cholesterol  from  peripheral  tissues  to  the  liver,  that  is,  reverse  cholesterol  transport.  The  return  of  plasma  HDL  CE  to  the  liver  may  involve  transfer  to  TRL  by  CETP,  selective  uptake  of  free  and  esterified  cholesterol  (i.e.,  cellular  uptake  of  HDL  lipid  without  protein  degradation),  or  uptake  of  holo-HDL  particles.  An  authentic  HDL  receptor,  scavenger  receptor  BI  (SR-BI),  is  highly  expressed  in  the  liver  and  steroidogenic  tissues,  where  it  mediates  the  selective  uptake  of  HDL  lipids.Plasma  HDL  levels  show  an  inverse  relationship  to  atherosclerotic  cardiovascular  disease.  Underlying  this  relationship  is  the  ability  of  HDL  to  promote  the  efflux  of  cholesterol  from  foam  cells  in  the  arterial  wall  and  to  mediate  reverse  cholesterol  transport.  Transgenic  mouse  studies  strongly  support  an  antiatherogenic  role  of  HDL,  and  are  consistent  with  increased  reverse  cholesterol  transport  as  the  underlying  mechanism.  Antiatherogenic  properties  of  HDL  may  also  be  related  to  its  ability  to  inhibit  the  retention,  aggregation,  and  oxidation  of  LDL  in  the  arterial  wall.  Humans  with  low  HDL  often  have  increased  levels  of  TRL;  in  some  cases,  low  HDL  is  likely  a  marker  for  a  metabolic  predisposition  to  accumulate  atherogenic  remnants  of  TRL.  Subjects  with  low  HDL  typically  have  increased  catabolism  of  apo  A-I,  a  process  that  may  be  driven  by  increased  core  lipid  exchange  between  HDL  and  TRL.  In  other  cases  low  HDL  may  be  a  marker  of  an  inflammatory  state  involving  the  vessel  wall.Transgenic  mouse  models  have  proven  invaluable  in  elucidating  the  metabolism  of  HDL  and  its  relationships  to  atherosclerosis.  Human  apo  A-I  transgenic  mice  show  increased  HDL  cholesterol  and  have  human-like  subspecies  of  HDL  in  plasma.  Importantly,  apo  A-I  transgenic  mice  are  resistant  to  the  development  of  early  atherosclerotic  lesions  in  response  to  an  atherogenic  diet.  Moreover,  the  apo  A-I  transgene  inhibits  the  development  of  both  early  and  late  complex  atherosclerotic  lesions  in  apo  E  knockout  (KO)  mice.  These  experiments  provide  compelling  evidence  for  a  direct  ...