What is a Lipoprotein?
-Spherical complexes of Lipids and Proteins.
-Function: too keep lipids soluble as they transport them
-Function: transporting lipids to and from tissues
What are the types of Lipoproteins?
Chylomicrons
VLDL
LDL
HDL
How are TAG's, Cholesterol Esters, free FA's and Dietary Lipid Soluble Vitamins transported in blood?
Abumin:
-Free Fatty Acids
Lipoproteins:
-TAG's
-CE
Chylomicron Remnant:
-Dietary Lipid Soluble Vitamins
-TAGS
When TAG's in Adipose cells are broken down, how do they get to the Liver?
FA's are stored after a meal in TAGS in fat cells and can reach the liver during fasting as free fatty acids via ALBUMIN.
What is in the inner and outer core of Lipoproteins?
Inner Core: Hydrophobic
-TAGS
-Cholesterol Esters
Outer Core: Hydrophillic
-phospholipid monolayer (PC)
-Free Cholesterol
-Proteins
The different types of Lipoproteins differ in ___ and ___?
Size and Density
Compare Densities of :
CM
VLDL
LDL
HDL
Density from Low to High:
CM
VLDL
LDL
HDL
*
More protein, less TAGS adds density
*
Which Lipoprotein has the highest [TAG], [Cholesterol], [Protein]?
TAG: CHylomicrons, VLDL
Cholesterol: LDL
Protein: HDL
Chylomicrons Structure
-Mostly TAGS
-Also Cholesterol and Cholesterol Esters and Lipid Soluble Vitamins
-Apo-48
Chylomicron Function
-Assembled in Intestinal Mucosal Cells and enter lymph
-Carry DIETARY TAGS to peripheral tissues
VLDL Structure
-High [TAG], Cholesterol, CE
-Apo-100 needed to provide release into blood
VLDL Function
-Released from Liver to get rid of Hepatic TAGS
-Provides CE for other cells inside of LDLs
-Carry Lipids from Liver to Peripheral Tissues
Which Lipoproteins lead to "high TAG's in blood"?
Chylomicrons and VLDL
LDL Structure
-formed form VLDL
-High [Cholesterol, CE], Low [TAG]
LDL Function
-To provide CHOLESTEROL to the peripheral tissues
or
-Return it to the Liver
HDL Structure
-Smallest
-High [Protein]- apolipoproteins, CE and Cholesterol, phospholipids
HDL Function
-They are capable of picking up cholesterol, carried internally, from cells
- A plasma enzyme called LCAT converts the free cholesterol into cholesteryl ester which is then sequestered into the core
-HDL transports cholesterol mostly to the liver or stero
Lipoprotein Lipase
-Extracellular Enzyme bound to capillary walls of heart, skeletal muscle, and adipose tissue
-Cleaves TAGS inside Lipoproteins
What anchors Lipoprotein Lipase?
Heparin Sulfate
Which Lipoproteins does Lipoprotein Lipase cleave TAGS?
Chylomicron and VLDL
LPL needs ____ for Activation
Apo-CII
Compare LPL in HEART vs FAT cells?
HEART:
-small KM
-High Affinity
-breaks down TAGS even at [low]
-FA's NOT stored
FAT:
-Activated by Insulin (high glucose)
-High Km, Low Affinity
-breaks down TAGS at [high lipoprotein]
-FA's STORED in fat cells
What is the effect of Insulin on LPL?
It enhances LPL synthesis and placement in capillary endothelium surface
Apolipoproteins Function
-Provide Recognition sites for cell surface
-Serve as activators or coenzymes for enzymes
-Required as structural component
-Can be transferred freely btwn Lipoproteins
5 Major Classes of Apolipoproteins
...
Chylomicron Circulation
-Chylomicrons are released from Intestinal Mucosal Cells and enters Lymph
-CM join blood circulation at Thoracic Duct
-HDL gives Apo-CII and Apo-E to CM
-LPL cleaves DIETARY TAGS in CM
-FA's are used by heart or stored in Fat cells
-The big CM becomes sma
Apo-48 vs Apo-100
Apo-48:
-synthesized in Intestinal Mucosal Cells
-needed for the release of Chylomicrons into Lymph
Apo-100
-Synthesized in liver
-needed for the release of VLDLS into Blood
Post translational Modification of Apo-100
Apo-100 undergoes mRNA editting by Cytidine Deaminase to form and EARLY STOP codon which creates Apo-48
Apo-100= Liver
Apo-48= Intestine
VLDL Circulation
-VLDL released from Liver
-VLDL obtains Apo CII and Apo E from HDL
-LPL cleaves TAGS in VLDLs
-Apo CP II is given back to HDL
-IDL's and remnant of VLDL's formed
-1/2 of IDL's taken up into Liver (via Apo-E ,LRP, or LDL Recptor)
-1/2 IDL's form LDL's (Apo
What happens if ALL the IDL's were changed to LDL's?
The [LDL] in the blood would be too high
What are the 3 ways that IDL's can be taken up into the Liver?
Via and Remembant Receptor on the Liver which recognizes:
1) Apo E
2) LRP (LDL-Receptor Related Protein)
3) LDL-receptor (Apo-100/ApoB)
What are the Isoforms of ApoE?
Apo-E1
Apo-E2 (Binds poorly to receptor)
ApoE3( most common)
What happens to IDL after it is formed?
-It is taken into the the liver
-Hepatic Lipase cleaves TAGS in IDLS
What happens to LDL's after formed?
-70% are taken up into the Liver via LDL receptors
-LDL's are also taken up by cells wich contain LDL receptors in plasma membranes when they need CHOLESTEROL
What is the explanation behind a high serum [LDL] after a cholesterol rich meal?
In the liver, after a cholesterol rich meal, the Chylomicron remnants lead to a high free cholesterol level in the liver
The high cholesterol levels reduce LDL-receptor synthesis so LESS LDL will be taken up into the cell
How does LDL enter the Liver?
They do so by binding to cell surface membrane LDL receptors that recognize Apo-100.
What occurs to chemically modified LDL's?
They are uptaken by Macrophages via Macrophage Scavenger Receptors
These receptors (SR-A) can mediate the endocytosis of chemically modified LDL
Macrophage Scavenger Receptor Activity
1) LDL becomes oxidized (not recognized by LDL receptors)
2) Macrophages consume modified LDL's and become Foam Cells
3) Foam Cells accumulate cause build up of fibrofatty atheroma
4) Plaque formation can lead to atherosclerosis
What receptor in macrophages allows the endocytosis of oxidized LDL?
Scavenger Receptor (SR-A)
LDL- Pattern A vs Pattern B
LDL Pattern A:
-larger
-less dense
LDL Pattern B:
-smaller
-more dense
*
Risk Factor for Coronary Heart Disease
*
Why is LDL Pattern B a risk factor for CHD?
Bc they are small and dense, they can penetrate more easily into the endothelium
Lipoprotein (a)
Lp(a)"
-a risk factor for CHD
-very similar to LDL but has an additional Apo (a)
-shows unusual structure of "Kringles
Apo (a)
-A glycoprotein covelently linked to Apo B-100 (disulfide)
-Structural analog of Plasminogen so it competes with Plasminogen for binding to Fibrin
-Able to reduce removal of blood clots which could trigger MI or Stroke
Risk Factors for CHD
Total Cholesterol: HDL > 5
High LDL:HDL Ratio
TAG: HDL >4
oxLDL
High LDL-B
Lp (a)
How are oxLDL formed?
Oxidation of Phospholipids or Apo B-100
LDL receptor Endocytosis Steps
1) LDL receptors are negatively charged glycoproteins that are aligned in a coated pit
2) They recognize Apo B-100 in LDL (positively charged)
3) The uptake is via Endocytosis
4) CE's are cleaved to form free Cholesterol (cholesterol stored) by ACAT
5) LD
LDL Receptor and [Cholesterol]
At High free [Cholesterol], the ACAT is activated and a reservoir of CE is formed
ACAT
Acyl CoA Cholesterol Acyl Transferase
If free cholesterol left, down regulation of :
-synthesis of HMG CoA Reductase
-synthesis of LDL receptors
What happens to the SCAP-SREBP complex at high [Cholesterol]?
THe SCAP-SCREBP complex is retained in the ER membrane and SREBP cannot enter nucleus
Which Apo Lipoprotein is involved with the release of Chylomicrons?
Apo B-48
Which Apo Lipoprotein is involved with the release of VLDL?
Apo B-100
Which Apoprotein is needed for recognition by remnant receptor?
ApoE
Which Apo Lipoprotein is involved with HDL apoprotein donation to chylomicrons or VLDL?
Apo C-II and Apo E
Which Apo Lipoprotein is involved with Activation of LPL?
Apo C-II
Which Apo Lipoprotein is involved with Activation of Lecithin: Cholesterol Acycltransferase?
Apo A-1
If cholesterol is not required immediately by the liver, then it is esterified to CE by _____.
ACAT
Acyl CoA Cholesterol Acyl Transferase
Hyperlipidemias
-Group of diseases where abnormally high levels of lipoproteins are found in serum
-Type I-IV
Acquired Hypertriacylglycerolemias and Hypercholesterolemia is often associated with...
-Hypertension
-Untreated Diabetes
-Alcohol Abuse
......................................
-Hypothyroidism
-Nephrotic Syndrome
-Obstructive Liver disease
Normal serum TAG levels ____ with AGE.
Normal serum total cholesterol levels ____ with AGE.
TAG= Increase
Cholesterol= Increase
Hypertriacylglycerolemias is characterized by:
Abnormally high levels of Lipoproteins that have a high % of TAGS (Chylomicrons and VLDL's)
CAUSE: Reduced LPL, defective Apo C-II, increased release of VLDL's
Hypercholesterolemias is characterized by:
Abnormally high levels of lipoproteins with high % of cholesterol and CE's (LDL and Lipoprotein remnants)
CAUSE: defective LDL receptos, Apo-E deficiency
Type I Hyperlipidemia
Hyperchylomicronemia"
-High levels of chylomicrons after FAST
-Genetic defect of LPL or Apo-CII, or LPL inhibitor
-Eruptive Xanthoma's (skin, butt), creamy layer on top of blood
Type IIa Hyperlipidemia
Familial Hypercholesterolemia"
-High levels of LDL with normal VLDL
-Defective LDL-receptor
-CHD Risk
-Zanthoma over tendon
Very RARE
Type IIb Hyperlipidemia:
Familial Combined Hyperlipidemia"
-High serum LDL & VLDL
-Very complex: overproduction of Apo B-100, VLDL, defective clearance of LDL
-more common than type I
Type III Hyperlipidemia
Dysbetalipoproteinemia"
-High remnants of: IDL and Chylomicron due to Apo E deficiency
-High blood [Cholesterol] and [TAG]
-Palmar Xanthomas, and eruptive Xanthomas Elbows, Knees
accelerated atheroscelorisis
What is the function of LCAT?
-an enzyme that cleaves fatty acid out of PC of HDL membrane and esterifies it to free cholesterol in blood
-special way to form CE from free cholesterol in blood
What Apolipoprotein is needed for Reverse Cholesterol Transport performed HDL?
Apo A-1
What can use free cholesterol in blood to form cholesterol esters and how?
LCAT cleaves fatty acids from PC of HDL membranes and esterifies it to free cholesterol in the blood
Where in the body is Lipoprotein Lipase synthesized?
Lipoprotein LIpase is mainly synthesized in myocardial cells, fat cells, and skeletal muscle cells.
The enzyme is then exported but stays bound to capillaries
Which hormone favors lipoprotein synthesis?
In Fat cells ONLY, LPL synthesis and release is favored by INSULIN
What Proteoglycan anchors Lipoprotein Lipase to endothelium wall?
Heparan Sulfate (GAG)
Why is the Lipoprotein Lipase bound to capillary wall?
The fixed location ensures that the released FA's from TAGs are directly available to the heart, skeletal muscle, and tissue
The LPL isoform of the heart has a _____(higher/lower) affinity for TAG's than the isozyme found in Fat Cells.
Higher affinity, it will be attracted to TAG's even if there is very little. FA's are used right away NOT stored.
Since the Fat cells use FA's to store as TAG, what is needed for the synthesis of TAG's?
Glycerol, which they get by the uptake of glucose (DHAP, G-3-P) thru GLUT 4 transporter
Where is LCAT synthesized and active?
-LCAT is synthesized by the LIVER and is released as free enzyme into the blood stream
-The site of action is in the blood close to cells that need to get rid of free cholesterol from plasma membrane
Which enzyme is needed to fill HDL with cholesterol esters?
LCAT (activated by Apo A-1)
Which Lipoproteins use Apo E for recognition by remnant receptor of Liver?
Chylomicron remnant
IDL (remnant of VLDL)
LDL-receptors recognize ____ in LDL.
Apo B-100
In what situation is LDL often modified by oxidants?
When it is trapped in blood with less access to antioxidants like Vitamin E and Vitamin C or Uric Acid.
How are macrophages changed to foam cells?
Macrophages that take up an excess of oxLDL become foam cells
What is released by foam cells and what is it's consequence?
Foam cells release growth factors and cytokines.
This stimulates the migration of smooth muscle cells
Ox-LDL is formed from LDL at _____ (high/low) serum LDL levels.
High
What are the percentages of Uptake of IDL's, LDL's by Liver?
-50% of VLDL=IDL's are taken up by Liver
-50% VLDL=LDL
-70% of LDL's taken up by LIVER
-30% cholesterol distributed to tissues
How are VLDL's converted to LDL's?
Hepatic Lipase, which is bound to Liver capillaries, converts it.
What happens to Chylomicrons when it enters lever?
The Cholesterol Ester is cleaved to form free cholesterol.
What is found in [high] in blood in Hyperlipidemia Type IIa and IIb?
Hyperlipidemia Type IIa is characterized by high LDL.
Hyperlipidemia Type IIb is characterized by high LDL and high VLDL.
Both, hyperlipidemia Type IIa and IIb are common.
Apo-48 represents what % of Apo-100?
48%
Reverse Cholesterol Transport by HDL
-Net movement of cholesterol from peripheral tissues back to the liver via HDL lipoproteins.
-Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1.
- ApoA-1 acts as an acceptor, and the phospholipid component of HDL acts as a
Hyperlipidemia Type IV
Hyperprebetaliporptoeinemia"
-High VLDL
CAUSE: LPL deficiency, overproduction of VLDL
Hyperlipidemia Type V
Mixed Hypertriacyleglycerolemia"
-High VLDL & Chylomicrons
-Patients serum has creamy layer on top
Describe the separation of HDL, LDL, VLDL, and chylomicrons in electrophoresis?
Most Protein=Most Negative (faster movement towards Anode)
HDL-LDL-VLDL-Chylomicrons
*
Chylomicrons are still at origin bc of very little protein
*
Statin Drugs
-Used for treatment of Hypercholesterolemia
-Inhibition of HMG CoA Reductase
How can Statin drugs lead to Rhabdomyolisis?
Less cholesterol synthesis interferes with synthesis of IPP and FPP which reduces synthesis of Dolichol (N-glycosylation) and CoQ (ETC) = Rhabdomylosis
*
skeletal muscle tissue break down
*
What is another possible treatment of Hypercholesterolemia?
Plant Stanols and Sterols
-displace cholesterol from micelles during absorption into intestinal mucosal cells
Ezetimibe
Drug that blocks a transporter protein to reduce cholesterol absorption
What is the reasoning to use Bile Acid Sequestering Drugs for treatment of Type IIa Hyperlipidemia?
-Type IIa caused by deficiency of LDL receptor synthesis
-The treatment is going to optimize the LDL-receptor synthesis as much as possible
-Bile Acid Resins bind and trap Bile Acid/Salts in the intestines and lead to excretion of Bile Acids/Salts into fe
What is the Major Function of HDL?
-Reverse Cholesterol Transport
-mobilization of free cholesterol from plasma membranes or arterial walls and delivery as CE to the liver or steroidogenic tissues
What is a discoidal Nascent HDL?
-A newly formed HDL which is not filled with CE's and so take son a discoidal shape
-Contains Apo A-1, Apo CII, Apo E
What is the main phospholipid in the Nascent HDL?
PC
Transformation of HDL
Nascent HDL-newly formed
HDL-3: after filled with more CE's;
HDL-2: uptake of phospholipids for outer layer monolayer (LARGER) from blood
Which HDL delivers CE's to Liver?
HDL-2
How do HDL cells pick up cholesterol from cells?
-They are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1).
-A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholest
How does LCAT form Cholesterol Ester?
-The LCAT uses fatty acid in position 2 of lecithin (PC) of HDL monolayer
and free cholesterol in the blood
-forms Cholesterol Ester and moves it immediately inside of HDL
HDL2 vs HDL3
HDL3:
-smaller
-provides Apo C-II and Apo E for VLDL and Chylomicrons
-uptake of CE's
HDL2:
-larger
-filled with MORE CE's + phospholipids for outer monolayers
-can interchange CE's for TAG's with VLDL
-delivers CE to liver/steroidogenic tissues
HDL can exchange ____ for _____ with VLDL .
Cholesterol Esters for TAGS
How are Cholesterol Esters of HDL taken up into Liver?
-Liver Scavenger receptors (SR-B1) and Hepatic Lipase are involved with the uptake of CE's from HDL-2 into Liver
What is the role of Hepatic Lipase in CE uptake into Liver from HDL?
After binding to SR-B1, the Hepatic Lipase opens the phospholipid layer of HDL 2 to allow CE's to enter liver
*
Phospholipase Activity
*
How can HDL3 be converted to HDL2
After Uptake of Phospholipids and action of LCAT (uptake of CE's).
Which protein allows for transfer of TAG's from VLDL into HDL in exchange for CE's?
CETP (Cholesterol Ester Transferase Protein) binds to both VLDL and HDL 2 and catalyzes exchange
*
TAGS and CE travel thru a Hydrophobic Channel
**
What are other special functions of HDL?
1) Potential Anti-antherogenic properties
2) Potential plaque stabilization properties
HDL & Anti-atherogenic properties
-Reverse cholesterol transport using LCAT and ABC-transporter which reduces LDL levels
-Contains enzymes that reduce LDL oxidation
HDL & Plaque Stabilization
1) HDL-mediated cholesterol efflux reduces plaque lipid content
2) HDL may reduce plaque macrophage content and activity and increase plaque smooth muscle content (preventing rupture)
Hypolipidemias
-RARE; deficiency in lipoprotein
1) Hypoalphalipoproteinemia
2) Abetalipoproteinemia
Hypoalphalipoproteinemia
Tangier's Disease"
-LOW serum HDL cholesterol
-Related to Obesity, Smoking, Statins
*
Orange Tonsils
What is the cause of Tangier's Disease?
Related to a defective cholesterol ABC transporter in the plasma membrane.
This leads to less substrate from LCAT and early degradation of Lipid poor Apo A-1 in blood=low HDL
Abetalipoproteinemia
-Low VLDL, LDL, & Chylomicrons
-Fat Malabsorption, TAG, Retinitis pigementosa
What is the cause of Abetalipoproteinemia?
Defect in microsomal TAG transger protein (MTP) which is needed for formation of VLDL or CM
Why convert Cholesterol to CE?
Cholesterol is amphiphatic so it can stay in the phospholipid monolayer
BUT it must be converted to CE in order to be more hydrophobic and remain in the core.
The Efflux of Cholesterol to HDL is regulated by ____.
ABC Transport Protein
The uptake of CE from HDL to Liver is regulated by ______.
SR-B1
SR-A vs SR-B
SR-A:
-Macrophages Scavenger Receptor for LDL
SR-B:
-Binds to HDL, transfers CE to Liver