24ªAula

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•  Lipoproteínas: Metabolismo das lipotroteínas 
•  Papel protector das HDL no processo aterosclerótico. 
Bibliografia 
•  Lodish H., Baltimore D., Berk A., Zipursky S.L., Matsudaira P., and Darnell J., Molecular 
Cell Biology (4ª Ed.), Freeman W.H. and Company (USA) (2000). 
•  Baynes J., and Dominiczak M.H., Medical Biochemistry (1ª Ed.), Mosby Int. Ltd (1999). 
•  Voet D. and Voet J.G. (2011) Biochemistry, 4 th edition, Wiley. Inc. 
Lipoproteínas 
Lipoproteins 
•  Several different classes of lipoproteins. 
•  Chylomicrons deliver dietary fats to tissues 
•  VLDL, IDL and LDL transport endogenously synthesized 
TAG (triacylglycerol) and cholesterol to tissues 
•  HDL remove cholesterol from serum and tissues and 
transports it back to the liver. 
•  VLDL, IDL, LDL, and HDL named based on their density. 
Low density lipoproteins have high lipid to protein ratios. 
High density lipoproteins have low lipid to protein ratios. 
Model Structure of a Plasma Lipoprotein 
  Each contains different kinds and 
amounts of lipids and proteins 
•  The more protein, the higher the 
density 
•  The more lipid, the lower the 
density 
  Each has different function 
Lipoproteins 
How can lipoproteins Differ? 
  They differ according to: 
1.  Composition of lipids to proteins 
2.  Size 
3.  Density 
Functions of Lipoproteins 
  Transport lipids in plasma by the protein portion 
(keep lipids soluble) 
  Transporting their lipid content to & from tissues 
Relative Composition of Lipoproteins 
CETP 
CETP 
Ciclos de Vida das Lipoproteínas 
O Colesterol circula no organismo em dois circuitos distintos 
  Esterification of cholesterol: 
  When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme 
phosphatidylcholine:cholesterol acyltransferase (LCAT) 
  LCAT binds to nascent HDLs, and is activated by apo A-1 
  LCAT transfers the fatty acid from carbon 2 of phosphatidylcholine to cholesterol. This produces a 
hydrphobic cholesteryl ester. As cholesterol esters accumulate in the core of lipoprotein 
L 
L 
L 
CETP 
CETP 
Papel protector das lipoproteínas HDL 
Reverse Cholesterol Transport 
HDL 
Major Classes of Lipoproteins 
•  Chylomicrons: 
–  Very large and very low density 
–  Transport lipids from intestine  adipose 
•  VLDL: 
–  Made in liver 
–  Transport lipids to tissues 
•  LDL: carry cholesterol to tissues 
•  HDL: 
–  Made in liver 
–  Scavenge excess cholesterol esters 
–  “Good cholesterol” 
Papel antiaterogénico das lipoproteínas HDL 
1.  Remove colesterol de células e tecidos extra-hepáticos, inclusivé paredes das 
artérias,e, eventualmente libertam o colesterol para o fígado, directamente 
através da capatção selectiva mediada pelo receptor SR-BI, ou indirectamente 
pela transferência do seu colesterol para outras lipoproteínas que são ligandos 
para receptores hepáticos; este transporte reverso de colesterol diminui, 
quer o colesterol intracelular nos macrófagos quer o colesterol total 
transportado pelo corpo, assim reduzindo a formação de células esponjosas; 
2.  O excesso de colesterol no fígado pode ser secretado para a bilis e, 
eventualmente, ser excretado pelo corpo; 
3.  As HDL per se e algumas enzimas plasmáticas associadas com as HDL 
(paraoxonase) podem suprimir a oxidação das LDL – reduzindo a captação 
pelos SRs dos macrófados das LDL e, assim, a formação das células 
esponjosas. 
4.  HDL tem propriedades anti-inflamatórias; 
5.  A ligação das HDL ao receptor SR-BI estimula a actividade da NO-sintase e, 
consequentemente, promove o aumento da produção de óxido nítrico (NO) 
(propriedades vasodilatadoras) que relaxa o músculo liso à volta das artérias e 
promove a dilatação do lúmen e, consequentemente, aumenbta o fluxo 
sanguíneo ajudando a prevenir a isquemia. 
Filme… 
Acções terapêuticas para diminuir 
as LDLs circulantes 
Hipercolesterolemia 
Familiar(defeito genético) 
Hipercolesterolemia 
Statins Cont’d
  Decrease LDL cholesterol, also have anti-inflammatory effects, 
improve endothelial dysfunction, stabilize atherosclerotic 
plaques, and have antioxidative properties 
  Risks: Muscular adverse reactions, hepatic/renal complications 
(e.g. muscle aches/cramps most frequent complaint) 
  Clear skeletal muscle damage in statin treated patients 
  All statins observed to cause myopathy 
  If discontinue use  effects reverse 
  High dose treatment shows positive effects but may be 
associated with increased side effects 
  Although a good way to treat high cholesterol, statins only treat 
less than 50% of patients with Cardiovascular Disease