Lipids and Lipoproteins Flashcards
what are the features of Isoprenoids
-three acetyl CoA (a 2 compound acetyl CoA) to generate a IPP (isopentenyl pyrophosphate) a 5 C compound
IPP which serves as a building block for synthesis of all isoprenoids
these include steroids, lipid soluble vitamins, ubiquinone, and prenyl groups to anchor proteins to Plasma membranes
what are the sources of Acetyl CoA
generated in Mitochondria via
- pyruvate
- fatty acids
- Amino acids
then transported to cytoplasm via the citrate shuttle
what is the back bone of steroids
six units of IPP to make a tetracyclic sterane ring
serves as back bone of steroids
what is the structure of cholesterole
Allicyclic compound made of 4 fused rings
has 27 carbons
and one hydroxyl group at C 3
characteristics of cholesterol
found in Plasma membranes and things like bile acids and bile salts, vitamin D, steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)
cells cant degrade steroid nucleus of cholesterol
must be used biochemically or excreted by liver, Excess cholesterol can lead to athersclerosis
how much cholesterol is produced
0.75 - 1 gram made in the liver but also in small intestine, adrenal cortex, ovaries, testes, and skin’
biosynthesis inversely proportional to dietary intake
what does cholesterol need to be made
18 acetyl CoA 18 ATP 16 NADPH and will finish with 27 carbons
Phase 1 of making cholesterol
Acetyl CoA
Acetoacetyl CoA
HMG CoA
-enzyme used to make this is HMG CoA synthetase
Mevalonate
-enzyme used to make this HMG CoA reductase (rate limiting step)
then to IPP
Phase II of making cholesterol
IPP to make Squalene
lanosterol
cholesterol
what inhibits HMG CoA reductase and some side effects
Statins used to lower amount of cholesterol
-lovastatin, simvastatin, pravastatin, atorvastatin
can lower up to 60 percent of cholesterol
very strong competitive inhibitor
- Ki is 5-45 nM compared to natural 4 uM
- binds in cytosol of the catalytic domain
also has a hypocholesterolemic action by increasing SREBP maturation to increase transcription of LDL receptor and help clear cholesterol in blood via LDL mediated endocytosis
Myotoxic side effects: duue to inhibit production of IPP which is important in the production of ubiquinone (CoQ) impairing mitochondrial function and then degeneration of myocytes
-can supplement this though
what is the fate of cholesterol
cholesterol is esterfied to cholesterol esters by the enzyme Acyl CoA cholesterol acyltransferase (ACAT)
then is packaged into VLDL and released into the blood to go to various organs to be used
what is the regulation on Cholesterol synthesis
regulated at rate limiting step
- Direct inhibition by free fatty acids, bile acids, and statins
- Covalent modifications: enzyme is inactive when phosphorylated and activated when dephosphorylated
in low energy, high AMP, activate AMPK will phosphorylate HMG CoA reductase
- insulin will activate HMG CoA reductase
- glucagon will deactivate HMG CoA reductase
also is controlled by transcription, translational , and post translational
Mechanism of Transcriptional control
HMG CoA reductase has a sterol regatory element in its promotor region
- SREBP (binding proteins) in inactive form
- activates SCAP (SREBP clevage activating protein
- in presence of cholesterol, SREB-SCAB complex will be retained in ER due to binding of INSIG
-if low cholesterol, SREBP-SCAP complex will go to golgi and undergo proteolysis and mature to have SREBP translocate to nucleus to bind SBE to increase transcription of HMG CoA reductase
function, and structure of Lipoproteins
serve as vehicles for transport of cholesterol, cholesterol esters, TAGS, and fat soluble vitamins
outer layer: monolayer of phospholipids, free cholesterol, and apolipoproteins
inner core: packed with TAGS, cholesterol, cholesterol esters
- lipoprotiens help transfer and deliver TAG
- lipoproteins help with Cholesterol homeostasis
- apolipoproteins Targeting signals/ligands
- apolipoproteins activate various enzymes
what are the 5 different lipoproteins
Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate density lipoproteins (IDL)
LOw density lipoproteins (LDL) (bad cholesterol)
High density lipoproteins (HDL (good cholesterol)
this is also same goes for size in that order
what 5 lipoproteins contains the most percentage TAGS?
cholesterol?
Proteins?
Chylomicrons have most TAGs but least protein
LDL: highest percentage of cholesterol relatve to size
HLDL: least TAGS but highest protein make up
structures found on a chylomicron and its properties
ApoB-48 : facilitates transport
ApoC-II : activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver
Exogenous and formed from dietary fats
- largest
- least dense
- High TAG
structures found on VLDL and properties
ApoB-100: uptake into cells
ApoC II: activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver
- made in liver
- packaged with TAGs and cholesterol
structures found on IDL
ApoB-100: uptake into cells
ApoE: facillitates uptake into liver
Structures found on LDL and properties
ApoB-100: uptake into cells
bad cholesterol
no TAGs
lots of cholesterol
structures found on HDL and properties
ApoA-1: activates enzyme that esterfies cholesterol
ApoC-II: activates capillary lipoprotein lipase
ApoE: promotes uptake into hepatocytes
good cholesterol
- smallest
- most dense
- high protein and phospholipid content
Chylomicron processing
1) nascent chylomicrons are assembled with dietary lipids in the small intestine and transported through the lymp back to the blood stream
2) additional apoproteins are added to create a mature chylomicron (apoC-II and ApoE are supplied by HDL)
3) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released back to HDL
4) remnants areendocytosed by the liver via binding to ApoE to its receptor
Type I and III proteinemia
these affect either the ApoC-1, ApoE or the capillary lipoprotein lipase
VLDL, IDL and LDL processing
1) VLDL are assembled in the liver and released into the bloodstream
2) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released and now just IDL remains
3) Cholesterol in IDL is delivered back to the liver via binding ApoE to IDL receptors in liver cells
half of IDL lose more TAG via action of the hepatic lipoprotein lipase and then will lose ApoE to become LDL
4) LDL deliver their cholesterol load to the liver and peripheral tissue of ApoB-100 to LDL receptors on target cell
how does LDL play a key role in cholesterol metabolism
LDL is the major carrier of cholesterol in blood
LDL can carry 1500 cholesterol ester molecules
shell has ApoB-100 which is recognized by receptors in target cells
role of LDL is to transport cholesterol to peripheral tissues and regulate the synthesis of cholesterol
how does the uptake of LDL occur
receptor mediated endocytosis
ApoB-100 will bind onto an LDL receptor and then get brought into the endosome
then the LDL receptor will release the LDL in the endosome due to the change in the pH
one class of mutation that results in familial hypercholesterolemia generates receptors that are unable to release the LDL cargo
HDL processing
1) nascent HDL is synthesized in the liver and the small instestine
2) picks up cholesterol from peripherla tissues
3) LCAT esterfies cholesterol and these will enter the HDL making it spherical
4) HDL receives ApoC-II and ApoE from chylomicrons
the HDL will transfer the cholesterol to VLDL, IDL, LDL in exchange for TAGS and phospholipids via the CETP (cholesterol ester transfer protein)
HDL delivers its cholesterol load to the liver
Beneficial effects of HDL
High HDL correlates positively with reduced risk of CAD
-because important for maturation of chylomicrons by supplying ApoC-II and ApoE
plays an important role in reverse cholesterol transport by removing cholesterol from parts of tissues in the body and bringing them back to the liver
-scavenges and removes LDL-cholesterol from periphery and transports it to liver where it can be recycled and processed
antioxidant, anti-inflammatory, antithromotic, and nitric oxide inducing properties
HDL- C levels are increased by weight loss, excersise and smoking cessation
what protein is important for reverse cholesterol transport and can be mutated
Cholesterol-transport protein in endothelial cells and macrophages, APCA1 (ATP-binding cassette transporter, subfamily A1)
loss of this leads to a disease called Tangier disease
-HDL deficiency and accumulation of cholesterol in macrophages and premature athersclerosis
Type I familial hyperchylomicronemia
Deficiency in apoC-II or defective lipoprotein lipase
increase in Chylomicrons
increase in Triacylglycerol
Type IIa and IIb familial hypercholesterolemia
LDL receptor is completely IIa or partially IIb defective
increase in cholesterol
increase in triacylglycerol: normal IIa and increased in IIb
increase in LDL
increase in VLDL for IIb
Tangier disease
hypolipoproteinemia
defect in transporter that supports cholesterol pickup by nascent HDLs
decrease in HDL
Type I hyperlipoproteinemia
Hyperchylomicronemia
inabillity to hydrolyze TAGs in chylomicrons and VLDL
cause: deficiency in capillary lipoprotein lipase or ApoC-II, an essential part of LPL complex and necessary for enzyme activity
Primary is an LPL deficiency manifiests in infancy
ApoC-II deficiency post adolescence
Plasma TAG levels are greater than 1000 mg/dL
creamy appearance of blood
clinical symptoms: abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas
treatment = low fat diet
Type II Hyperlipoproteinemia
familial hypercholesterolemia
causes: defect in LDL receptor resulting in uptake of LDL via receptor mediated endocytosis
increased cholesterol in blood
high LDL undergoes oxidation, oxLDL leads to an inflammatory response leading to cardiovascular disease such as athersclerosis
impaired abillity to reckognize ApoB-100 on LDL
normal cholesterol = 130-200
heterozygous = 300-500
homozygous = >800
untreated lead to death of CAD
physical symptoms: Xanthomas, corneal , deposits in eyes, and angina pectoris
Heterozygous respond to diet, statins, and bile binding resins
Homoygous: LDL apheresis and liver transplant
Plasma Cholesterol and Athersclerosis
LDL-C levels correlate positively with Cardiovascular disease
LDL-C accumulates nder the endothelial cells lining blood vessels
-there the LDL will modify to become oxidized LDL
-this oxLDL accumulates in the vessel wall and lead to endothelial injury leading to even more influx of LDL into arterial wall
this increased vascular permeabillity and leukocyte adhesion
- oxLDL initiates an inflammatory response
- macrophages up take the ox LDL but become engorged forming foam cells
Foam cells become trapped in the walls to form plaques
-death of foam cells, platelet adhesion, and recruitment of smooth muscle cells leads to further development of arterial plaque that eventually leads to athersclerosis
narrowing of arteries by the plaques lead to heart attacks
