Cholesterol Transport Flashcards
Chylomicrons (CMs)
Deliver dietary TGs from intestine —> peripheral tissues
VLDLs
Deliver endogenous TGs from liver to peripheral tissues
LDLs
Delivers cholesterol from liver to peripheral tissues
Bad cholesterol
HDLs
Mediate reverse cholesterol transport from periphery to liver
Good cholesterol
CM higher in TG or cholesterol?
TGs
CMs are created in the intestinal epithelial cells during a well-fed state
Lipoprotein lipase (LPL)
Tissues that need fFA secrete this enzyme
It is activated by ApoC-II (which is on the CM surface)
Allows the cell to extract FA from the TGs stored in the CM
Where do CM remnants go?
After being depleted of its FA stores by peripheral tissues…called remnants
Returned to the liver
In the liver,
TGs and cholesterol are repackaged into what?
VLDLs (higher in TG than cholesterol)
Well-fed state: the liver can also synthesize TGs and cholesterol
Fasting state: live can absorb excess FFAs coming from adipocytes, re-esterify them…and package them into VLDLs.
In other words…the liver is ALWAYS making VLDLs —> secreted into the blood
fate of VLDLs remnants (TG-depleted)
Returned to the liver to be repackaged again
…
Converted into LDLs (higher in cholesterol than TGs)
—> they deliver cholesterol to the extrahepatic tissues or are taken up by liver to be repackaged again
ApoC-II
Tissue source: liver
Lipoprotein distribution: CM, VLDL, IDL, HDL (all except LDL and CM remnant)
Function: activates LDL enzyme
ApoB-100
Tissue source: liver
Distribution: VLDL, IDL, LDL
Function:VLDL assembly and secretion, structural protein, ligand for LDL receptor
ApoB-48
Tissue source: intestine
Distribution: CM, and CM remnant
Function: assembly and secretion of CMs from the intestinal mucosa
ApoA-1
Tissue source: liver and intestine
Distribution: HDL
Function: activates LCAT enzyme, and structural component
ApoE
Tissue source: liver
Distribution: CM, CM remnant, VLDL, IDL, HDL (no LDL)
Function: ligand for binding several lipoproteins to…
—> LDL receptor
—> LDL receptor-related protein (LRP)
—> possibly to a separate ApoE receptor
Life cycle of CMs
- Immature CMs (nascent) are produced in the intestinal epithelium
—> have ApoB-48 so that it can be assembled - Nascents secreted into the blood
- ApoC-II and ApoE are transferred from HDLs they encounter
- Cells secrete LDLs, which are activated by Apo-CII and thus degrade the TGs in the CM
- ApoC-II is returned to the HDLs
- CM remnants (still contain ApoE) bind to receptors on liver and are uptaked into liver
- Ultimately redistributed as VLDLs
Fate of VLDL and LDL
- Liver assembles nascent VLDLs
—> has ApoB-100 - Nascent VLDLs are secreted into the blood and ApoC-II and ApoE are transferred from HDLs encountered
- Cell secrete LDLs…activated by ApoC-II (like in CMs) and are depleted of TGs
- As getting depleted VLDL —> IDL —> LDL
- ApoC-II and ApoE are returned to the HDL
- Leaving ApoB-100 as the major apolipoprotein on LDL
- ApoB-100 = ligand for LDL endocytosis to deliver cholesterol to tissues
- Remaining LDL are taken up by liver via ApoB-100 by same mechanism
Note***VLDL remnants can return to liver to be repackaged via ApoE…or converted to LDLs (#4-5)
- LDLs have ApoB-100 which binds to receptors on extrahepatic tissues and liver to mediate uptake —> to deliver cholesterol
Receptor-mediated endocytosis of LDLs
ApoB-100 = LDL receptor ligand and binds to the receptors
LDL is endocytosed and becomes a endosome
Endosome —> lysosome…and cholesterol is extracted for various uses
Cholesterol will regulate its own levels in the cell by which two mechanisms?
- Shuts down synthesis of cholesterol by inhibiting HMG CoA reductase
- Shuts down synthesis of LDL receptors —> inhibits uptake of LDLs
Target of statin drugs
HMG CoA reductase
Cholesterol is (?) for storage
Esterfied
Fate of HDL (reverse cholesterol transport)
- Nascent HDLs made in liver and small intestine
—> concentrated in phospholipids
—> low in cholesterol at this point
—> donates ApoE and ApoC-II to CMs and VLDLs - ApoA-1 activates PCAT/LCAT
- PCAT/LCAT grabs cholesterol from the cell suing transporter ABCA1
—> cholesterol is esterified to one of the FAs of PC - Liver uptakes HDL cholesterol (via scavenger receptor) to be excreted or redistributed
OxLDL
Enhanced by oxidizing agents: superoxide, nitric oxide, hydrogen peroixde
Anti-oxidizing agents: vitamin E, ascorbic acid, beta-carotene
Can damage the endothelial cells that line blood vessel
Recruits macrophages to damaged cells —> become foam cells —> harden the artery
Familial hypercholesterolemia (FH)
General
AD
Elevation of plasma LDL
Causes:
- Dysfunctional LDL receptor
- Increased LDL receptor degradation
- ApoB-100 defects reducing receptor affinity
Problems:
1. Premature artherosclerosis and coronary heart disease
Heterozygous FH
High fasting LDL (250-500 mg/dL)
Normal TGs
CHD onset in 4th-5th decade
Treatment: 1st = statins (inhibit ability to make cholesterol)…statins increase LDL receptor synthesis
2nd = bile acid sequestrants…
—> bile acid is made from cholesterol
—> meds inhibits recycling of bile acids…so have to make more from cholesterol
Homozygous FH
Really really high LDL (500-1200)
Xanthomas = fatty deposit pockets under skin
CHD within 1st 2 decades
Unresponsive to statins
LDL apheresis to remove ApoB-containing lipoproteins (CM, VLDL, IDL, LDL)
Cholesterol ranges
Normal: < 100 mg/dL
Near optimal: 130-159
High: 160-189
Very high: >190
Familial dysbetalipoproteinemia
High cholesterol and TGs in blood
Causes:
- Deficiency or defective ApoE
- Unable to clear CM remnant of VLDL remnant
Symptoms:
- Xanthomas
- Atherosclerosis
- Angina
- Peripheral artery disease
Treat with low calorie and low fat diets
A-betalipoproteinemia
Do not have beta producing lipoprotein complexes
= Bassen-Kornzweig Syndrome
= microsomal TG transfer protein deficiency
(MTTP)
Essential for synthesis and secretion of ApoB-48 and 100)
Results = no absorption of vitamins ADEK…fat soluble vitamins
Symptoms
- Failure to thrive
- Diarhhea
- Star shaped RBCs
- Fatty stools
- Cannot balance
- Vision loss
Treatment = fat soluble vitamin supplments…medium chain FAs diet
Niemann-pick (Type C) disease
Pertain to the lysosome after LDL receptors are taken up
AR
Progressive neuro degeneration and lysosomal buildup of cholesterol (and other lipids) in the CNS, liver, and spleen
Mutations in NPC1 and NPC2
—> involved in the release of cholesterol from later endosomes and lysosomes after degradation has occurred
—> leads to buildup of cholesterol
—> feedback inhibition is impaired…no inhibition of synthesis of cholesterola nd LDLr
Symptoms:
- Cant move
- Hepatomegaly
- Splenomegaly
- Jaundice
- Seizures
INBORN ERROR OF METABOLISM - so will see early on in life
Treatment = miglustat (new)
Prognosis is poor
Tangier disease
Rare AR
HDL deficiency (ApoA-1)
Loss of ABCA1 function
Kidneys take over sole function of extract cholesterol - not good at it
Cholesterol accumulates in the tissues
CM and VLDL do not get ApoC-II from HDLs—> hypertriglycemia
Virtually no HDLs of LDLs…but accumulationg of VLDLs
Symptoms:
- Neuropathy
- Orange-colored tonsils
- Splenomegaly
- Corneal clouding
- Enlarged liver
. Type 2 diabetes
Treatment = symptomatic and supportive (splenonectomy)
Alzheimer’s disease
Cholesterol cannot cross the BBB…must be made and redistributed within teh CNS
—> ApoE = main protein that helps to redistribute cholesterol in the CNS
—> ApoE can either decrease or increase risk of Alzheimers
Isoforms of ApoE:
- ApoE-2 = may provide protection against the disease…develope it later in life
- ApoE-3 = most common…neutral role
- Apo-4 = common, increases risk of developing disease at earlier onset
Hypercholesterolemia and CHD
HC increases risk of CHD
Treatment aimed to lower total and LDL cholesterol while increasing HDL
Want 4:1 (total cholesterol(LDL):HDL ratio)
Treatments:
- Diet, lifestyle changes
- Statins
- Bile acid sequestrants
- Ezetimibe —> blocks cholesterol absorption
- Niacin and gemfibrozil (decrease TGs, increase HDL cholesterol)
Atherogenic dyslipidemia
Combination of 3 abnormalities
- Increased VLDL TGs
- Decrease HDL
- Increased LDL
= dyslipidemia profile
Associated with:
- Obesity
- Metabolic syndrome
- Insulin resistance
- Type II diabetes formation
- Hypertension
Smith-lemli-optiz syndrome (SLOS)
Most common genetic defect of cholesterol biosynthesis
Defect in 3beta-hydroxysterol-delta7-reductase
Results in increased 7-DHC and decreased cholesterol in circulation
Morphogenic abnormailies
- Microcephaly
- Dysmorphic carniofeatures
- Polydactyly
- Congenital heart disease
Defects are due to lack of cholesterol to post-translational modification of Hedgehog (Hh) protein
With implication in signaling in embyronic patterning
