Lipoprotein complexes and cholesterol transport Flashcards
In the liver, ___ and ___ are repackaged into very low density lipoprotein complexes (VLDLs). What can happen to VLDL from there?
TGs and cholesterol are repackaged into VLDLs, which are secreted into the blood.
Lipoprotein lipase may deplete teh TGs and the VLDL remnants are returned to the liver
OR
Converted into LDLs, which go back to the liver OR supply cholesterol to the extrahepatic tissues.
Lipoprotein complexes
Different percentages of phospholipid + cholesterol + TGs
Apolipoprotein on the outer surface
Most of the apolipoproteins are synthesized in the liver. Which two are synthesized in the intestine?
ApoA-1 - Intestine AND liver
ApoB-48- Intestine
Which apolipoproteins are the only ones that isn’t used by chylomicrons?
ApoA-1
&
ApoB-100
ApoA-1: Tissue source, lipoprotein distribution, function
ApoB-48: Tissue source, lipoprotein distribution, function
Intestine
Chylomicrons
Assembly & secretion of chylomicrons from intestinal mucosa
ApoB-100: Tissue source, lipoprotein distribution, function
Liver
VLDL, IDL, LDL
- VLDL assembly & secretion
- Structural component of VLDL, IDL, LDL
- Ligand for LDL receptor
ApoC-II: Tissue source, lipoprotein distribution, function
Liver
Chylomicrons, VLDL, IDL, HDL
Activates lipoprotein lipase (LPL)
ApoE: Tissue source, lipoprotein distribution, function
Liver
Chylomicron remnants, VLDL, IDL, HDL
- Ligand for binding several lipoprotiens to the LDL receptor, the LDLreceptor-related protein, and to a separate ApoE receptor
Path of chylomicrons
How does it provide fFAs to extrahepatic tissues and then cholesterol to the liver?
- Synthesis w/Apo-B-48 in the intestine to transport lipids
- Enter lymphatic system then blood, where it takes ApoC-II & ApoE from HDL
- ApoCII activates lipoprotein lipase –> TGs are hydrolyzed to fFAs that go to muscle, adipose, or other extrahepatic tissues and glycerol that goes to the liver for glyceroneogenesis or gluconeogenesis.
- Different LPLs have different Kms!
- CM remnants (depleted of TGs) are now mostly cholesterol and give their ApoC-II back to HDLs, then head to the liver using ApoE as a ligand.
ApoC-II on the chylomicron activates LPLs to hydrolyze TGs in muscle, adipose, and other extrahepatic tissues.
LPLs in different tissues have different Kms.
Which LPL has the higher Km - adipose or muscle?
Adipose LPL has the higher Km, so it digests TGs only when [chylomicrons] are high.
Muscle LPLs have the lower Km to allow continual access to FAs even at lower [chylomicron].
Which has more TG content- chylomicrons or VLDLs?
Chylomicrons have more TGs
Fate of VLDL and LDLs
- Liver synthesizes VLDLs from TGs (mostly) + cholesterol + ApoB-100 (required for synthesis & secretion)
- Get an ApoC-II and ApoE from HDLs in the blood
- ApoC-II activates an LPL, providing fFAs for extrahepatic tissues & losing TG content –> IDL –> LDL
- ApoCII and ApoE are returned to the HDL
- The remaining ApoB-100 is the major ligand for LDL receptor-mediated endocytosis so the LDL can deliver cholesterol and its minor remaining TGs to peripheral tissues.
LDL uses its ApoB-100 to cause receptor-mediated endocytosis - In the endosome, the LDL receptor is recycled back to the surface while the LDL complex is broken down in the lysosome –> everything is used, including cholesterol.
What happens if you have excessive cholesterol? Deficient cholesterol?
Excessive cholesterol:
- Inhibits HMG-CoA reductase to stop making cholesterol
- Inhibits synthesis of new LDL receptors to stop bringing it in
- Activate ACAT, which esterifies the excess cholesterol to FAs
Deficient cholesterol reverses all of these.
why is LDL is the “bad” cholesterol involved in atherosclerosis and coronary heart disease?
- When it oxidizes into oxLDL, it damages artery walls
- Monocytes adhere and become macrophages that engulf the oxLDL through upregulated scavenger receptors –> becomes a foam cell
- Foam cells accumulate and release growth factors & cytokines that stimulate migration of smooth muscle to enter the intima and secrete collagen –> atherosclerotic plaque
- Plaque can grow and rupture into the artery as a thrombus that grows until it occludes the artery
Familial hypercholesteremia (FH) / Type II hyperlipoproteinemia
- AD
- High LDL cholesterol caused by a dysfunctional LDL receptor, increased degradation of the LDL receptor, or ApoB-100 defects
Contrast heterozygous vs homozygous FH
Onset
Symptoms
Tx
-
Heterozygous FH:
- Increased fasting LDL, but normal TGs
- Onset when 40-50yos
- Tx:
- Statins decrease cholesterol synthesis and increase LDL receptor synthesis to lower serum LDL
- Bile acid sequestrants also reduce serum LDL by using it for bile acid synthesis
-
Homozygous FH:
- EXTREMELY high fasting LDL
- Childhood
- Xanthomas in hands, wrists, elbow, knees; coronary heart disease
- Tx: LDL apheresis removes VLDL, IDL, and IDL
Dysbetalipoproteinemia / type III familial hyperlipoproteinemia
- High cholesterol & TGs (CM remnants) in the blood due to defeciency or defective ApoE
- ApoE2 isoform binds poorly to LDL receptor, so homozygous E2/E2 can’t clear out the LDL/IDL & CM remnants
-
Broadening of the B band in electrophoresis because CM, VLDL, IDL, and LDL all use ApoB lipoproteins
- (HDL complexes use ApoA)
- Onset at 20yo or older
- Xanthomas, atherosclerosis, angina, ischemia, peripheral artery disease
- Tx: low-cal, low fat diets. Maybe drugs
What is the function of HDLs?
HDLs return excess cholesterol from extrahepatic tissues to the liver for excretion OR recycling in reverse cholesterol transport.
Abetalipoproteinemia
- AR
- Can’t make CM, VLDL, or LDLs because of a MTTP deficiency (essential for synthesis & secretion of ApoB lipoproteins).
- Without ApoBs –> malabsorption of dietary fats & vitamins ADEK
- Onset as an infant
- failure to thrive; diarrhea; acanthocytosis; steatorrhea; impaired nervous ssytem; poor muscle coordination; ataxia; retinitis pigmentosa; vision loss
- Tx: vitamin & linoleic acid supplements, avoid LCFAs
Niemann-Pick (Type C) Disease
- AR mutation in NPC1 & 2, which release cholesterol from endosomes and lysosomes
- Cholesterol builds up in lysosomes instead of going to the membrane –> cell synthesizes and exocytosis more LDL receptors –> makes things worse
- Onset can occur whenever, but prognosis is poor
- Dementia, seizures, hepatomegaly, dystonia, ataxia, tremors…..
- Tx: Miglustat; low-cholesterol diet
Fate of HDL
How does it take excess cholesterol from nonhepatic cells and deliver it to the liver for excretion or periphery for reidstribution?
- Synthesis in liver and intestine; concentrated with phospholipids, ApoA1, ApoE, and ApoCII
- Donates ApoE & ApoCII to CMs and VLDL
- In the body, they take up phoshpolipids and free cholesterol using ABCA1 transporter
- ApoA1 activates PCAT to esterify cholesterol to FAs from phosphatidylcholine in the HDL phospholipid monolayer
- Cholesterol esters are more soluble and stored inside the HDL
- CETP can transfer some of the cholesterol esters to VLDL remnants for redistribution
- Eventually, it binds the liver through a Scavenger receptor and a hepatic lipase takes its cholesterol & cholesterol esters
Tangier disease
- Reduction in plasma HDL
-
Loss of function in the ABCA1 transporter
- –> HDLs are rapidly degraded
- –> CM & VLDL particles can’t get their ApoCII
- Impaired LDL formation from VLDLs
- Early onset CVD, hypertriglyceridemia, neuropathy, big orange tonsils (full of cholesteryl-esters), splenomegaly, corneal clouding, atherosclerosis, T2D
Because of the BBB, the CNS has to make its own lipoprotein complex transport system.
The most abundant apolipoprotein in the CNS is ___, synthesized by glial cells.
ApoE
Different ApoE isoforms & Alzheimer’s
ApoE2 lowers the risk; would cause later onset in life (protective)
ApoE3 is most common, but neither increases/decreases risk
ApoE4 increases the risk of AD; causes earlier onset
Hypercholesterolemia (increased total & LDL cholesterol) increases the risk of ___
Coronary heart disease
The ___ cholesterol ratio measures the risk for developing heart disease.
We want to keep the ratio at 4:1 or lower.
total cholesterol : HDL cholesterol
The goal is to keep the ___ ratio above 0.3
HDL : LDL ratio
Tx for hypercholesterolemia
- Dietary, behavioral, and life style changes
- Low fat
- High oleic acid (olive oil) to lower total and LDL cholesterol
- Bile acid sequesterants like cholestyramine to excrete bile acids and cholesterol
- Statins to prevent cholesterol synthesis
- Ezetimibe to block cholesterol absorption
- Niacin/gemfibrozil to decrease plasma TGs while elevating HDL
Atherogenic dyslipidemia is a combination of… and is a major risk factor for…
Combination of
- Increase in TGs
- Decrease in HDLs
- Increase in LDLs
Major risk factor for CVD*, obesity, metabolic syndrome, T2D, and HTN
Smith-Lemli-Opitz Syndrome SLOS
-
Defect in 3B-hydroxysterol delta7-reductase (part of cholesterol synthesis)
- 7-DHC builds up
- Cholesterol deficiency
-
Birth defects (microcephaly, dysmorphic craniofeatures, polydactyly, congenital heart defects) due to
- Lack of cholesterol for post-translational modification of Hedgehog protein needed in embryonic patterning
- Increased 7DHC alters fluidity of lipid rafts that impair Hh interactions with other membrane receptors
How do you differentiate between heterozygous and homozygous familial hypercholestermia and why does this matter?
Herozygous has a plasma LDL of 200- 500
Homozygous has a plasma LDL of 500+
It matters because homozygous is unresponsive to statins- prefers LDL apheresis
