Lecture 53 Flashcards
Lipoproteins: Structure, Function, and Metabolism
lipoproteins overview and classes
- spherical macromolecular complexes of lipids and specific proteins (apolipoproteins)
- their role is to transport cholesterol, fats, and fat-soluble compounds via the blood (all hydrophobic so need protein carriers)
- 4 major classes: chylomicrons, very low density (VLDL), low density (LDL), and high density (HDL)
pg 1373-1374
lipid transport in the blood
- as part of lipoproteins: triacylglycerols, phospholipids, steroids (cholesterol), and sphingolipids
- bond to serum albumin: free fatty acids
pg 1375
cholesterol
- free cholesterol: maintains fluidity in membranes
- cholesterol ester: storage and transport form
pg 1376
lipoprotein core
- composed of hydrophobic neutral lipids:
- triacylglycerols (TAGs)
- cholesterol esters (CE)
pg 1377
lipoprotein polar lipid surface
- composed of a monolayer of amphipathic lipids:
- phospholipids (phosphatidylcholine - PC and sphingomyelin - SM)
- unesterified (free) cholesterol -> fluidity
- polar head likes water, 2 hydrophobic FA tails face core
pg 1378
lipoprotein amphipathic apolipoproteins (Apo)
- more than 11 different types of Apo proteins found in humans (ApoA, ApoB, ApoC, ApoD, etc)
- several subclasses of each type of Apo protein
- peripheral and integral
pg 1379
apolipoproteins in humans
from this slide -> Apo B
- Apo B-48 from intestine, associated with chylomicrons, structural protein for chylomicrons
- Apo B-100 from liver, associated with VLDL, IDL, LDL -> structural protein, ligand for LDL receptor
pg 1380
lipid composition and size of lipoproteins
- chylomicrons biggest, but least dense
- HDL smallest, but most dense
pg 1381
chylomicrons
- size may vary depending on meal content
- largest in size, least dense
- contain highest percentage of fat (90%)
- produced by gut cells
pg 1382
VLDL
- similar to chylomicrons, but produced by hepatocytes
- smaller and more dense
- contain a high percentage of fat reflecting their primary role to distribute fat away from the liver to peripheral tissues
- 20% cholesterol
pg 1382
LDL
- contain highest percentage of cholesterol (50%)
- reflects their role to distribute cholesterol to tissues
- produced from VLDL via lipolysis in the bloodstream
pg 1382
HDL
- highest percentage of protein (40%)
- reflects one of the roles as a reservoir of Apo-s
- second highest percentage of cholesterol reflective of their role in the reverse cholesterol transport
- capable of exchanging Apo proteins with other lipoproteins
- “good cholesterol”
- take up all excess cholesterol and take back to liver for removal
pg 1383
understanding lipid lab values
- total cholesterol: cholesterol attached to lipoproteins (chylomicrons, VLDL, LDL, IDL, HDL)
- triglycerides: chylomicrons, VLDL, IDL
- HDL cholesterol: HDL only
- CHOL/HDL ratio: total cholesterol divided by HDL
- LDL calculated (lipid panel): total cholesterol minus HDL and VLDL
- direct LDL cholesterol: measured
- VLDL cholesterol: VLDL only
pg 1384
exogenous lipoprotein metabolism
- gut forms nascent chylomicron (initial large molecule released into lymph)
- lipoprotein lipase in circulation converts to chylomicron
- chylomicron goes through circulation and leaves chylomicron remnant behind (what is left after delivering lipids to peripheral tissues)
- chylomicron remnant goes to liver
- ALSO: HDL collects cholesterol from tissues, undergoes Apo exchange with chylomicrons, delivers cholesterol to liver
pg 1385
endogenous lipoprotein metabolism
- liver produces VLDL
- VLDL in body becomes IDL and then LDL
- IDL and LDL go to tissues and eventually back to liver
- HDL participates in reverse cholesterol transport (RCT) -> collects excess cholesterol from peripheral tissues
pg 1386
metabolism of chylomicrons
- intestinal mucosal cells secrete nascent TAG-rich chylomicrons produced from dietary (exogenous) lipids -> has apo B-48
pg 1387
production of chylomicrons and VDL: step 1
synthesis of Apo B
- B-apolipoprotein gene undergoes transcription and RNA editing to form Apo B-100 and Apo B-48
- Apo B-100 (full length) formed in liver hepatocytes to produce VLDL
- Apo B-48 (48% of length) formed in intestine due to early stop codon -> packages lipids from diet (in enterocytes) into chylomicrons
pg 1388
production of chylomicrons and VDL: step 2
Co-translational lipidation of Apo B
- lipids from enterocyte cross ER membrane via microsomal TAG-transfer protein (MTP) to join Apo B-48 and form the Apo B particle
- triacylglycerols also use MTP to join Apo B particle and form larger Apo B particle
pg 1389
lomitapide (Juxtapid)
- small molecule inhibitor of MTP that has been approved for the treatment of certain patient populations
- population: individuals that are homozygous for mutations in the LDL receptor and are not effectively treated with drugs such as alirocumab and statins
pg 1389
production of chylomicrons and VDL: step 3
maturation and secretion
- in the right conditions, the larger Apo B particle leaves the endoplasmic reticulum and goes to the golgi apparatus
- when perfectly lipidated and packaged, it is secreted into the blood stream
- if missing something OR not the right size and shape, it will undergo lysosomal degradation
pg 1390
abetalipoproteinemia (Bassen-Kornzweig syndrome)
- defect in the microsomal TAG-transfer protein (MTP)
- autosomal recessive -> rare
- near complete absence of the apo B-containing lipoproteins
- affects the absorption of dietary fats, cholesterol, and fat-soluble vitamins
pg 1391
abetalipoproteinemia symptoms
- appear in the first few months of life
- failure to gain weight and grow at the expected rate
- diarrhea
- abnormal star-shaped red blood cells
- fatty, foul-smelling stools that may contain large chunks of fat and/or blood
- later in childhood -> impairment of the CNS function, poor muscle coordination, progressive retina degeneration to near-blindness (due to deficiency of vitamin A, retinol)
pg 1391
metabolism of chylomicrons pt 2
part of exogenous pathway
step 2. apo C-II and apo E are transferred from HDL to the nascent chylomicron (now has apo B-48, C-II, and E)
step 3. extracellular lipoprotein lipase, activated by apo C-II, degrades the TAG in chylomicrons
step 4. apo C-II is returned to HDL
step 5. CE-rich chylomicron remnants bind through apo E to specific receptors on the liver and are endocytosed
pg 1392
metabolism of VLDL, IDL, and LDL
part of endogenous pathway
1. liver secrete nascent, TAG-rich VLDL particles containing primarily endogenously synthesized lipids
2. apo C-II and apo E are transferred from HDL to the nascent VLDL
3. extracellular lipoprotein lipase, activated by apo C-II, degrades the TAG in VLDL (now IDL)
4. apo C-II and apo E are returned to HDL (removed from IDL) -> some IDL with apo E attached goes back to liver
5. LDL binds to specific receptors on extrahepatic tissues and on the liver and are endocytosed
pg 1393
fibrates
- used to lower TAG levels
- act through PPARα to…
- increase the expression of LPL (lipoprotein lipase)
- decrease apo C-III concentration
- increase HDL by increasing the expression of apo A-I and apo A-II
pg 1393
familial hyperchylomicronemia (Burger-Grutz syndrome)
- deficiency of lipoprotein lipase (LPL)
- autosomal recessive
- more common in areas of the province of Quebec
- symptoms: elevated plasma TAGs even in the fasted state, xanthomas (skin depositions of lipid), and pancreatitis
pg 1394
hyperproteinemia type III (broad beta disease)
- there are three common isoforms of apo E in humans -> apo Ee2, apo Ee3, and apo Ee4
- caused by homozygosity for apo Ee2, a genetic variant that does not bind to hepatic apo E receptors
- autosomal recessive
- symptoms: chylomicron remnants and IDLs remain in blood, elevating both, TAGs and cholesterol; xanthomas and early cardiovascular disease are common
pg 1395
metabolism of HDL
see slide
pg 1396,1398
LCAT role in metabolism of HDL
lecithin:cholesterol acyltransferase (LCAT)
- synthesized and secreted by the liver
- acts in the circulation to transfer of a fatty acid from the 2-position of lecithin (phosphatidylcholine, PC) in the phospholipid shell of the HDL particle to the 3-hydroxyl group of cholesterol, forming a cholesterol ester
- necessary in order to trap the cholesterol ester to the core of the HDL particle
pg 1397
CETP role in metabolism of HDL
CETP (cholesterol ester transfer protein) -> acts to simultaneously transfer TAGs from VLDL/IDL to HDL and cholesterol esters from HDL to VLDL/IDL
- the greater the concentration of triacylglycerol-rich lipoproteins in the blood, the greater the rate of these exchanges
- the CETP reaction, under high levels of TAG-rich lipoproteins, generates elevated levels of HDL3, which are leass atheroprotective than HDL2
- CETP inhibitors are currently being evaluated as a means of increasing HDL2 levels, with limited success
pg 1399
Tangier disease
- defect of the ABCA1 protein
- autosomal recessive
- very rare
- symptoms: significantly reduced HDL, mild hypertiglyceridemia, disturbances in nerve function (neuropathy) and enlarged, orange-colored tonsil
pg 1400
Norum disease
- defect of the LCAT protein
- total loss: familial LCAT deficiency
- partial loss: fish-eye diseae
- autosomal recessive, very rare
- inability of HDl to take cholesterol from cells due to loss of esterification capability
- symptoms: decreased levels of plasma cholesterol esters and lysolecithin; abnormal LDL (Lp-X) and VLDL; diffuse corneal opacities, swelling of optic nerve, xanthelasmas, targt cell hemolytic anemia, and proteinuria with renal failure
pg 1400
