Lipoproteins Flashcards
1
Q
What must lipids be packaged into to transport them through the blood stream?
A
lipoproteins
2
Q
what is plasma? layers of lipoproteins? (2)
A
- cells that have been removed from blood
- mix of proteins
- negative on top to positive on bottom- more charge makes run faster
- lower density on top and high density on bottom
- chylomicron on top and HDL on bottom for both
3
Q
Lipoprotein general structure? (3)
A
- amphipathic
- core of non polar hydrophobic lipids such as TG and cholesterol ester (cholesterol attached to long chain fatty acid)
- shell of amphipathic phospholipids and unesterified cholesterol which surrounds the core and is in contact with aqueous blood
- specialized proteins (apoproteins or apolipoproteins) are amphipathic having polar and non polar aspects, some apoproteins recognize specific receptors on target cells that act as docking stations
- cholesterol levels affect solubility of membrane
4
Q
classification of lipoproteins? (4)
A
- chylomicrons
- VLDL
- LDL
- HDL
- IDL
- classified by size, buoyancy, types of associated lipoproteins
5
Q
chylomicron classification? (4)
A
- largest size, most buoyant
- lowest density
- lowest charge
- majority of non polar molecules inside are TGs (dietary fat)
- contain ApoB48 apoproteins which are synthesized and packaged with nascent chylomicrons in intestinal epithelial cells
- chylomicrons acquire later other apoproteins from HDL, including ApoCII, ApoE
- transport dietary TG
6
Q
VLDL classification? (4)
A
- very low density lipoproteins
- majority of lipids inside are TGs, but not as much as chylomicrons
- smaller than chylomicron, but next largest
- contain ApoB100 apoproteins, which are synthesized and packaged with nascent VLDL in liver cells
- VLDL acquire other apoproteins from HDL, including ApoCII and ApoE
- transport endogenous derived TG
7
Q
LDL classification? (4)
A
- low density lipoproteins
- smaller and less dense
- have least amount of TG and largest amount of cholesterol esters
- derived from VLDL
- after VLDL releases majority of TG, they become IDL (intermediate density) and with further loss of TG, IDL becomes LDL
- LDL contains ApoB100, but have given back ApoCII and ApoE to HDL lipoproteins
8
Q
HDL classification? (4)
A
- high density lipoproteins
- very small, highly dense
- have few TGs and large amounts of cholesterol esters and protein, depending on life cycle
- contain ApoA apoproteins as well as other apoproteins, ApoCII and ApoE
- HDL is considered good lipoproteins because they have carry cholesterol away from tissues to the liver, and carry and distribute apoproteins to other lipoproteins for their function
9
Q
Functions of lipoproteins? (8)
A
- transport lipids through blood
- chylomicrons are packaged in small intestine from dietary sources of lipids, to tissues
- VLDL is packaged in liver from endogenous sources, either newly synthesized or recycled lipids, to tissues
- these two are composed mostly of TG
- adipose mobilize out to muscle and liver
- HDL transports mostly cholesterol from peripheral tissues back to liver
- LDL carries cholesterol to the peripheral tissues
- this allows homeostasis of lipid in body
10
Q
What situations arise where lipids are not carried on lipoproteins?
A
- low energy circumstances when TG is mobilized from adipose tissue as fatty acids to be used for energy, they are transported through blood on albumin
- they are carried to tissues for quick energy source, rather than taking time and energy necessary to package lipoproteins
- medium and short chain fatty acids do not need to be carried on lipoproteins to tissue
11
Q
What are apoproteins? function? (9)
A
- they are proteins that combine with lipoproteins either during packaging or are acquired later
- synthesized on the rough ER and packaged with lipids, cholesterol, or fat soluble vitamins on Golgi
- some lipoproteins may acquire apolipoproteins in the blood stream
- function to stabilize lipoproteins
- amphipathic, some amino acids can interact with hydrophobic lipids while other come into contact with hydrophilic blood stream
- some function as cofactors for enzymatic activity -some are enzymes
- some assist in transferring lipids among various lipoproteins
- some are recognized by cell receptors to allow lipoprotein to dock and taken into cell
- apoB100, apoB48
12
Q
ApoB100 vs ApoB48? (10)
A
- they are encoded by the same gene
- intestinal cells have a deaminase which changes RNA (by RNA editing) from C to U, thus changing CAA to UAA (stop codon), so B48 codes from only first half of transcript
- liver cells do not have a deaminase, resulting in a longer transcript and protein, ApoB100
13
Q
ApoE isoforms?
A
- E2, E3, E4 are common isoforms
- other rare variants
- generally has an anti atherogenic role through regulation of lipoprotein metabolism and transport
- E2 is most protective
- E3 is intermediate
- E4 is associated with alzheimers, atherosclerosis, diabetes
14
Q
Metabolism of chylomicrons?(5)
A
- synthesized in small intestine (contain ApoB48)
- during high lipid diet, lipids including TGs are digested using bile salts derived from cholesterol
- intestinal epithelial cells package large amounts of dietary TG into chylomicrons
- released into plasma
- as it travels through blood stream, HDL transfers ApoCII and ApoE to it
- ApoCII activates lipoprotein lipase (LPL), an enzyme located on inner leaflet of endothelial cells lining blood stream, to help deliver large loads of TGs to tissues
- because of the bulky hydrophobic structure of TG, they cannot directly enter cells so LPL breaks TG into three fatty acid and glycerol
- fatty acids directly enter the cell because of compatibility with cell membrane
- ApoCII is returned to HDL (chylomicron remnants)
- taken up by the liver through ApoE
15
Q
Metabolism of VLDL? (6)
A
- when dietary lipid intake is lower, liver synthesizes fatty acids from glucose and packages them as TGs in VLDLs
- VLDLs don’t carry as many TGs as chylomicrons (1/5 or 1/10 the size) - they are packaged with ApoB100 in liver
- liver can recycle any lipids remaining from chylomicron remnants by repackaging them, along with newly synthesized TG, into VLDL and sending them to the bloodstream
- liver can use lipids from chylo remnants for energy or incorporate them into lipid bilayers - after VLDL is in blood stream, HDL transfers ApoCII and ApoE to it
- LPL is activated by ApoCII and breakdown of TGs to fatty acids and glycerols
- ApoCII and ApoE are returned to HDL
- loss of TG leads VLDL to turn into LDL
- can be taken up by liver and other tissues - receptor can bind ApoB100 in C terminal, for uptake of LDL, VLDL
16
Q
Formation of LDL?
A
- as VLDL loses TGs, it becomes intermediate density lipoproteins (IDL)
- when more TGs are broken down, IDL becomes LDL
- all free or esterified cholesterol and phospholipids in VLDL are still present in IDL and LDL, but ratios of cholesterol esters to TG change with the loss of TG
- major difference is in the amount of TGs
- LDL transfers ApoCII and ApoE back to HDL for recycling
17
Q
What is the majority of LDL composed of? function?
A
- cholesterol and cholesterol ester
- function is deliver cholesterol to tissues
18
Q
Why do tissues need cholesterol? excess?
A
- need it for integrity and fluidity of lipid bilayers as well as for specialized products such as cholesterol derived hormones
- excess cholesterol inhibits further synthesis of cholesterol or synthesis of LDL receptors
- excess cholesterol can be converted to cholesterol esters for storage using cell enzyme, acyl CoA cholesterol acyltransferase (ACAT)
- ACAT attaches fatty acid from fatty acyl CoA to free hydroxyl of cholesterol to form cholesterol ester, non polar storage form
19
Q
What threat could increased LDL in blood stream cause?
A
- LDL delivered to tissues does not pose a threat of atherosclerosis
- increased LDL remaining in blood stream is basis for coronary heart disease
- bad lipoprotein
20
Q
How do cells take up LDL?
A
- all cells in the body can take up LDL through specialized receptors
- these receptors recognize ApoB100 and take up LDL by receptor mediated endocytosis
21
Q
Insulin effect on LPL?
A
- activates LPL in adipose and its placement in capillary endothelium
- decreases expression of LPL in muscle
- muscle and heart LPL is activated by glucagon and and epinephrine
22
Q
Regulatory functions of cholesterol?
A
- inhibits HMG CoA reductase enzyme
- inhibits LDL receptor biosynthesis
- activates ACAT (acyl CoA cholesterol acyltransferase)
23
Q
Metabolism of HDL? (7)
A
- nascent HDL particles originate in liver as lipid free or lipid poor apolipoproteins (ApoA-I)
- newly secreted particles acquire additional cholesterol and phospholipids via ABCA-1 on peripheral tissue
- ABCA-1(ATP binding cassette A 1) transfers proteins that use energy in the form of ATP in the transfer of oil, cholesterol, ions, drugs across membranes - HDL emerges from its interactions with ABCA-1 as pancake shaped nascent lipoprotein, composed of amphipathic lipoproteins, phospholipids, and some cholesterol
- its shape comes from majority of amphipathic molecules whose nature requires them to be in contact with aqueous blood
- HDL carries other specific proteins such as PCAT, CETP, PLTP - forms cholesterol esters (ApoA1 helps turn cholesterol into ester)
- transfers ApoCII and ApoE to lipoproteins
- taken up by liver
24
Q
major functions of HDL?
A
- transfer ApoCII and ApoE to VLDL and chylomicrons
- remove excess cholesterol from peripheral tissues and deliver it back to the liver (reverse cholesterol transport)
- anti atherogenic (good cholesterol)
25
Q
Lipoprotein lipase and ApoCII? (11)
A
- adipocyte LPL is induced by insulin
- LPL removes long chain fatty acid from chylo or VLDL
1. synthesized in rough ER
2. dimerized in Golgi
3. secreted to interstitial space
4. translocate to lumen of capillary
5. activated by ApoCII from HDL
6. hydrolyze TG to free fatty acids
26
Q
Chylomicron and ApoCII and ApoE? (12)
A
- made by intestinal epithelial cells
- derived from dietary lipids - nascent chylomicron (ApoB48)
- ApoCII activates LPL
- ApoE from HDL - removes long chain fatty acids from chylo and bring into tissue (muscle, adipose)
- becomes chylo remnants (ratio of TG:cholesterol is 1:1)
- ApoE assists chylo remnant docking at liver cells
- mostly TG, some cholesterol and PL
28
Q
Functions of cholesterol ester transfer protein (CETP)? (23)
A
- CETP is synthesized by many tissues, including liver and adipose and is bound to HDL particles in circulation
- CETP exchanges cholesterol ester on HDL for TG on VLDL
- CETP has both pro and anti atherogenic functions
- deficiency in CETP is associated with increased HDL levels
29
Q
Functions of phospholipid transfer protein (PLTP)? (23)
A
- PLTP exchanges TGs on HDL for phospholipids on VLDL
- ApoE may be essential for stabilizing PLTP
- PLTP is involved in HDL and VLDL remodeling, including conversion of HDL to large HDL2 and small lipid poor HDL particles
- PLTP has both pro and anti atherogenic functions
- deficiency in PLTP is associated with decreased HDL and ApoA1 levels
30
Q
Chylomicron process and lipoproteinemia? (13)
A
- nascent chylo contains 85% TGs inside, very specific protein ApoB48
- once in blood, receives ApoCII and ApoE
- ApoCII activates LPL to degrade TGs
- ApoCII leaves and returns back to HDL
- ApoE is for binding to liver to to break down remnants completely
- deficiency of LPL, lack of insulin, will cause Type 1 hyperlipidemia
- deficiency in ApoCII, more chylomicron in blood, Type 1 hyperlipidemia
- deficiency in ApoE, fail to bring into liver, Type III hyperlipidemia
- abetalipoproteinemia lacks ApoB48 and ApoB100 gene, deficient in making chylo, VLDL formation and absorption of fat soluble vitamins
31
Q
VLDL and ApoCII? (14)
A
- made by liver cells
- derived from liver synthesized fatty acid, plus any fatty acid from chylo remnants, packaged as TG - nascent VLDL has ApoB100 and (ApoCII and ApoE from HDL in blood stream)
- VLDL loses TG, turns to IDL, then LDL (ratio of TG: cholesterol is 1:1)
- IDL, LDL is taken up by liver and peripheral tissues via ApoB100
- LDL has tendency to penetrate and get stuck in blood vessels, causing oxidation of LDL, leading to disease
- mostly TG (less than chylomicron), some cholesterol and PL
32
Q
VLDL and lipoproteinemia? (15)
A
-problems cause hyperlipidemia
33
Q
ApoB100 mediated and LDL endocytosis and hyperlipidemia? (16)
A
- receptor is synthesized in rough ER, through golgi, and translocated to membrane
- LDL interacts with receptor to form cluster in coated pit to form vesicle to bring leftovers into cell
- inside, contents are separated, LDL on one part, vesicle is recycled
- LDL fuses with lysosome that contain many enzymes leading to degradation cholesterol to release free cholesterol inside cell to be used
- free cholesterol functions: - decreases LDL receptor synthesis
- inhibit HMG CoA reductase
- increase ACAT involved with cholesterol ester storage
34
Q
Effects of cell cholesterol on cholesterol metabolism? (17)
A
- inhibit LDL receptor synthesis, reduces uptake of cholesterol
- inhibit HMG CoA reductase, key enzyme in cholesterol synthesis in cell
- activate ACAT, takes fatty acid and put on cholesterol to turn into cholesterol ester
36
Q
HDL reverse cholesterol transport? (20)
A
- ApoA1 serves as docking site for periphery tissue
- ABCA1 moves lipid from tissue to newly synthesized HDL, gets bigger gradually
- carries back to the liver
37
Q
ApoA1 and PCAT? (21)
A
- HDL contains ApoA1 and PCAT (previously LCAT)
- ApoA1 activates PCAT, and PCAT esterifies cholesterol
- nascent HDL is disk shaped after taking more cholesterol, becomes more spherical
- PCAT deficiency called fish eye disease
38
Q
ABCA 1 and cholesterol loading? (22)
A
- ABCA1 member of big protein family
- ABC proteins use energy from ATP hydrolysis to transport material
- ABCA1 specifically involved with transporting cholesterol from peripheral tissues to HDL
- Tangier disease- mutation of ABCA 1, cannot eliminate cholesterols (yellow orange enlarged tonsils, very low HDL, enlarged liver and spleen)
40
Q
Summary of lipoprotein metabolism? (25)
A
pic
41
Q
Liver cholesterol metabolism? (26)
A
- takes up chylomicron remnants, carried back to liver and process remnants
- cholesterol is packaged with other lipids into chylomicrons - synthesizes new cholesterol using acetyl CoA from mitochondria, if diet is deficient (de novo synthesis)
- makes HDL (ApoA1)
- takes up HDL containing cholesterol, that HDL gathered from peripheral tissue - produces bile, secretes free extra cholesterol
- secretes VLDL
- VLDL loses TG to become LDL
- LDL delivers cholesterol to peripheral tissues including adrenal gland
43
Q
Biosynthesis of cholesterol process? (27)
A
- occurs in cytoplasm and enhanced by insulin
1. start with acetyl CoA
2. combine with two other acetyl CoA to HMG-CoA by HMG-CoA synthase - same as synthesis of ketone bodies
3. HMG-CoA is converted to Mevalonate by the enzyme HMG-CoA reductase - inhibited by cholesterol
- rate limiting step -this enzyme is the target of statin drugs
4. high energy 5 carbon isopentenyl pyrophosphate is formed
5. condensation of two 5 carbon isoprene units form the 10 carbon Geranyl pyrophosphate
6. further condensation results in 15 carbon Farnesyl pyrophosphate and then 20 carbon squalene
7. series of cycling reactions leads to Lanosterol
8. final product is cholesterol - cholesterol inhibits HMG-CoA reductase
- all carbons are derived from acetyl CoA
44
Q
Synthesis of ketone bodies vs cholesterol? (28)
A
pic
45
Q
Regulation of HMG-CoA reductase? (29)
A
- highly regulated
- cholesterol levels inhibits this enzyme
- SREBP and SCAP
- SRE is binding site on DNA that SREBP binds to
- cholesterol inhibits SCREBP
- levels of protein synthesis vs degradation
- covalent modification through phosphorylation (inactive) and dephosphorylation (active)
- insulin and thyroid hormone increase expression
- glucagon and glucocorticoids inhibits
46
Q
Atherosclerosis and CVD? (30)
A
-reversible in early stages
47
Q
Lipoproteins and atherosclerosis? (31)
A
- atherosclerosis, CHD, CAD describe a complex multifactorial genetic disorder closely associated with lipoproteins and cholesterol
1. LDL have tendency to penetrate blood vessel to get to extracellular matrix (ECM) and get stuck, they spend excess time in tissues
2. longer time LDL spends in ECM, increased danger of oxidation that results in oxidized LDL
3. endothelial cells consume oxidized LDL, releasing cytokines and growth factors and triggering inflammatory events
4. oxidation of LDL attracts monocytes which follow LDL out of blood into ECM
5. they become macrophages and engulf oxidized LDL, becoming foam cell
6. foam cells release growth factors to cause proliferation of smooth muscle in blood vessel wall and calcification of growing plaque
7. accumulation of foam cells with increased inflammation results in plaque formation (atheroma) on inner surface of major arteries
8. blood vessels become constricted, lose elasticity and decrease in blood flow, increased clot formation - oxidizing environment makes LDL worse
- superoxides, NO, H2O2 or other oxidants make it worse
- Vit E, ascorbic acid, beta carotene and other anti oxidants are beneficial
54
Q
Summary of effects of steatosis? (34)
A
- excess calories from saturated fats and fructose
- adipose tissue overgrowth
- oxidation is increased, too much stress
- could lead to lipotoxicity
- increased cytokines
- insulin resistance
56
Q
Alcoholism and fatty liver? (36)
A
- alcohol is mainly used by liver, not regulated
- end product is increased NADH
- disturbs balance of NADH to NAD
- TCA is slowed down
- drink a lot, dont eat much, lack glucose, forced to GNG, but increased NADH, pyruvate will turn into lactate (acidosis)
- ketogenesis to support energy needs
