Cholesterol Processing and Lipid Transport Flashcards
- Following formation of HMG-CoA, the remaining steps in cholesterol formation occur in the smooth endoplasmic reticulum.
- The first unique reaction in cholesterol synthesis is catalyzed by HMG-CoA reductase. This enzyme converts HMG-CoA to mevalonate. -HMG-CoA reductase is rate limiting and consequently highly regulated.
- The synthesis of cholesterol is divided into 4 stages.
Stage 1: mevalonate (6-carbon compound) is synthesized from acetyl CoA.
Stage 2: conversion of mevalonate to “active” isoprenoid (5-carbon) units with the aid of several ATP and loss of CO2. Six isoprenoid units condense to form squalene, the linear 30-carbon intermediate.
Stage 3: an enzyme complex, squalene epoxidase/cyclase, cyclizes squalene to yield lanosterol, the parent sterol.
Stage 4: cholesterol forms from lanosterol after 19 further steps, including the loss of 3 methyl groups.
•Key points of this pathway include
1) NADPH is required at all four synthesis stages;
2) ATP is utilized in stage 2; and
3) O2 is necessary for stages 3 and 4.
•NADPH is derived from both the malic enzyme reaction as well as from the oxidative branch of the pentose phosphate pathway.
•Major sites of cholesterol synthesis include liver, intestine, skin, and especially the endocrine glands that produce steroid hormones (i.e, adrenal cortex and gonads).
-Virtually all nucleated cells are capable of cholesterol synthesis.
- The reactions from acetyl CoA to cholesterol occur in the cytoplasm and on the smooth endoplasmic reticulum of the cell.
- Carbons for cholesterol synthesis require formation of acetyl CoA derived primarily from the beta-oxidation of saturated fatty acids.
- These carbons are carried from the mitochondrial matrix to the cytoplasm as citrate via the citrate transporter.
- Citrate is then lysed in the cytoplasm via citrate lyase to produce acetyl CoA and oxaloacetate.
- Citrate lyase requires coenzyme A (CoA) as a cofactor (coenzyme; cosubstrate) and ATP as a source of energy for the reaction.
- The oxaloacetate product is further processed to malate, which in turn is decarboxylated to pyruvate via malic enzyme with the concomitant production of NADPH (and CO2, not shown) that is required for cholesterol synthesis.
Cholesterol synthesis is controlled by regulation of HMG-CoA reductase - Glucagon and Insulin
•Regulation of cholesterol synthesis is exerted near the beginning of the pathway, at the unique HMG-CoA reductase step.
-Both the activity and the amount (i.e., number of molecules) of enzyme are controlled.
•Following food deprivation, the activity of HMG-CoA reductase is decreased acutely through posttranslational phosphorylation of the enzyme.
- This event is triggered by the elevated concentration of glucagon in the circulation.
- This action of glucagon explains the decreased synthesis of cholesterol during fasting.
•Conversely, in the fed state, insulin activates HMG-CoA reductase by causing removal of this phosphate from the enzyme by protein phosphatase.
Cholesterol synthesis is controlled by regulation of HMG-CoA reductase - Cholesterol
- The amount of HMG-CoA reductase (or LDL receptor) can be down regulated acutely by cholesterol, which binds to a sterol-sensing domain in the enzyme leading to activation of its proteolytic degradation.
- A separate chronic mechanism also exists whereby the concentration of HMG-CoA reductase is modulated by cholesterol, the endproduct of the pathway.
-A normal or high concentration of cholesterol represses formation of the HMG-CoA reductase enzyme (or LDL receptor) thereby lowering its amount.
Cholesterol synthesis is controlled by regulation of HMG-CoA reductase - Cholesterol and SREBP
•The gene for HMG-CoA reductase contains a regulatory DNA sequence in its promoter that must bind sterol regulatory element binding protein (SREBP) to be actively transcribed.
-In the absence of SREBP, transcription of the gene does not occur.
•A similar mechanism increases the amount of the receptor that recognizes LDL particles to promote their uptake by cells.
- Therefore both the HMG-CoA reductase and LDL receptor genes are regulated in a similar manner.
- These proteins work in tandem to increase the intracellular cholesterol concentration.
- De novo synthesis of cholesterol is enhanced by increased amounts of the reductase enzyme, and uptake of cholesterol into the cell is accelerated by having more receptors to pick up LDL that is laden with cholesterol ester.
- SREBP (sterol regulatory element binding protein) is responsible for signaling the synthesis of HMG-CoA reductase by binding to the DNA promoter region associated with coding for HMGCoA reductase or LDL receptor.
- Under conditions of normal or elevated cell cholesterol, SREBP is trapped in the endoplasmic reticulum (ER) membrane as part of a complex consisting of INSIG, SCAP (SREBP cleavage activating protein) and SREBP.
- Both INSIG and SCAP bind to cholesterol, which facilitates the binding of INSIG and SCAP. Thus SREBP cannot be mobilized and HMG-CoA reductase or LDL receptor transcription remains repressed.
- In this way, a high concentration of cholesterol represses its own synthesis and reduces the number of LDL receptors to decrease uptake of cholesterol ester into the cell.
•When the concentration of cholesterol in the cell becomes too low, INSIG and SCAP dissociate so that the SCAP-SREBP complex can move to the Golgi membrane for insertion.
-In the Golgi, two distinct proteolytic enzymes (S1P and S2P), cleave the SREBP from SCAP to release SREBP into the cytoplasm.
- SREBP then enters the nucleus and binds to the sterol responsive element (SRE) promoter region to induce the transcription of the gene encoding for HMG-CoA reductase or the LDL receptor.
- Consequently the cholesterol concentration increases in the cell to correct the cellular deficit.
Fates of Cholesterol
- Membrane structure
- Precursor of steroid hormones and vitamin D
- Esterification for storage
- Esterification for elimination
- Precursor to bile salts
Esterification for Storage or Elimination
- Esterification is catalyzed either by ACAT (acylCoA:cholesterol acyltransferase) for cell storage or by LCAT (lecithin:cholesterol acyltransferase) for transport by high-density lipoprotein (HDL).
- The ACAT and LCAT reactions provide major routes for storage and eventual elimination of cholesterol, respectively.
Cholesterol Elimination
- Ultimately, cholesterol enters the liver where it can be metabolized for excretion in the bile primarily as bile acids.
- A large proportion of the bile acids excreted from the gall bladder is reabsorbed into the portal circulation, taken up by the liver, and recirculated in the bile.
-In this way bile acids used in lipid absorption are conserved for the most part.
- The bile salts also play an important role in regulating their own formation from cholesterol.
- The hydroxylation of cholesterol to form 7 alpha hydroxycholesterol is the committed, as well as the rate limiting, step in the synthesis of bile acids.
- The reaction is catalyzed by 7 alpha-hydroxylase, which is expressed exclusively in smooth endoplasmic reticulum of liver. This reaction requires oxygen, NADPH and vitamin C (ascorbic acid).
7 alpha hydroxylase
•catalyzes the hydoxylation of cholesterol
cholesterol —> bile acids
- rate limiting step
- 7 alpha-hydroxylase enzyme is regulated by induction or repression.
- The enzyme is induced by cholesterol (feedforward effect) which binds to the liver nuclear receptor, LXR.
- The enzyme is feedback repressed by bile acids (feedback effect) which binds instead to the liver farnesoid receptor (FXR) to repress the 7 alpha-hydroxylase promoter on the gene.
•Hypercholesterolemia may be treated by interrupting the recirculation of bile acids back through the liver.
Removal of Cholesterol by Cells
- Though the detailed processing of HDL will be discussed later in the lecture, it is valuable at this point to understand how non-hepatic cells rid themselves of cholesterol for transport to the liver.
- The liver rids its cells of cholesterol primarily by conversion to bile acids that are excreted.
Removal of Cholesterol from Cells by HDL
- Besides cholesterol ester, HDL molecules contain lecithin, unique proteins and LCAT, for esterifying free cholesterol from cells.
- HDL in the circulation acquires cholesterol by employing LCAT to extract cholesterol from the plasma membranes of peripheral cells.
- This process of cholesterol removal by HDL is facilitated by an ATP-binding cassette protein (ABCA1) transporter called cholesterol efflux regulatory protein (CERP).
- CERP is activated by apolipoprotein A1, which is a protein component of HDL particles. CERP pumps cholesterol across the plasma membrane (i.e., flips the molecules from the cytoplasm to the membrane bilayer) and delivers them to HDL particles as a substrate for the LCAT enzyme found on these particles.
- Once loaded with cholesterol ester, HDL is transported to the liver where it dumps its cholesterol load for potential conversion to bile acids.
-Since HDLs are ultimately cleared by the liver, where cholesterol is converted to bile acids and excreted in bile, this step constitutes “reverse cholesterol transport” from cells to HDL, and is one of the crucial mechanisms whereby the body eliminates cholesterol.
Factors Influencing Cholesterol Balance Inside Cells - Intracellular Decrease
Decrease in the intracellular concentration of free (unesterified) cholesterol is a result of a combination of the following factors.
[a] The esterification of cholesterol by ACAT (acyl CoA:cholesterol acyl transferase) for storage in droplets.
[b] The utilization of cholesterol for the synthesis of other steroids, such as the hormones of the adrenal cortex and gonads, of bile acids in the liver, or of vitamin D in the skin
[c] The release of cholesterol for transport to the liver following:
i) trafficking to the plasma membrane (a process directed by the Golgi)
ii) pumping to the exterior surface by CERP (cholesterol efflux regulatory protein)
iii) transfer to HDL particles (promoted by LCAT)
Factors Influencing Cholesterol Balance Inside Cells - Intracellular Increase
Increase in the intracellular concentration of free cholesterol is a result of a combination of the following factors.
[1] The endocytotic uptake of low-density lipoproteins by the LDL receptor; also uptake of cholesterol-containing lipoproteins by scavenger receptors in macrophages, or by nonreceptor-mediated pathways and diffusion of free cholesterol from cholesterol-rich lipoproteins through the plasma membrane
[2] The synthesis of cholesterol by the pathway described earlier in these notes.
[3] The hydrolysis of cholesterol esters by the enzyme cholesterol esterase.
- The LDL receptor is found on the cell surface.
- The LDL receptor binds the LDL apoprotein B100, and the LDL, with its receptor, is taken up intact via endocytosis.
- The LDL particle is degraded in the lysosome/ late endosome. The protein component is degraded to amino acids, while the cholesterol ester is hydrolyzed by an acid hydrolase.
- The free cholesterol is then translocated by a protein (NPC-1) into the free cholesterol pool in the Golgi apparatus [w].
- This influx of cholesterol via internalization of LDL particles leads to the degradation and repressed synthesis of HMG-CoA reductase to shut down cholesterol synthesis.
- Additionally, the increased concentration of cholesterol represses the formation of new LDL receptors [x].
•Internalized cholesterol also stimulates ACAT activity [y] to enhance cholesterol storage and, via binding to LXR, induces the synthesis of CERP [z] to promote cholesterol efflux.
Therapies for Treating Hypercholesterolemia
- Statins
- Bile Acid Sequestering Resins
- Nicotinic Acid
- Fibrates
- Decreasing Intestinal Cholesterol Absorption
Therapies for Treating Hypercholesterolemia - Statins
- All statins are competitive inhibitors of hydroxyl-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in cholesterol synthesis. T
- hey inhibit the enzyme in the nano (10-9 ) molar range and work by blocking part of the site where HMG-CoA, the substrate, binds thereby limiting access of the substrate to the catalytic (active) site.
- By inhibiting HMG-CoA reductase, statins decrease synthesis of cholesterol by the liver and other tissues.
- This action in liver decreases the availability of cholesterol for the synthesis of very low-density lipoproteins (VLDL) particles that eventually become LDL particles.
- Additionally, slowing the rate of cholesterol synthesis lowers the concentration of intracellular cholesterol that leads to an increase in the number of LDL receptors and hence in the uptake of LDL from the blood.
-Hence the major overall effect of statins is to lower the plasma concentration of LDL and hence of circulating cholesterol.
- An additional benefit of statins is to raise the plasma concentration of HDL (‘good cholesterol’) by increasing the production of apolipoprotein A1, that activates CERP.
- Statins provide significant benefits to a broad range of patients at risk for coronary heart disease and this benefit in some seems independent of the circulating LDL concentration in the patient.
- Despite the undeniable benefits of statins, myopathies seem to be an issue for all or most statins and can even lead to a fatal rhabdomyolysis.
-Myopathies are monitored by testing for changes in the blood concentration of the skeletal muscle isoform of creatine kinase.
•Additionally physicians are cautioned to be aware of possible medication interactions between statins and other lipid lowering medications such as niacin and fibrates.
Therapies for Treating Hypercholesterolemia - Bile Acid Sequestring Resins
- As noted above, cholesterol is excreted through the formation of bile acids in liver. Therefore increased conversion of cholesterol to bile acids leads to a reduction in blood cholesterol.
- As with decreased liver synthesis of cholesterol, lowering the intracellular cholesterol concentration will lead to increased uptake of LDL from the blood.
- The conversion of cholesterol to bile acids can be increased by interrupting the enterohepatic circulation of bile acids.
-The enterohepatic circulation recycles bile salts to the liver where they normally repress the synthesis of the 7 alpha - hydroxylase enzyme.
•Plasma cholesterol can be significantly reduced by the use of the oral bile salt sequestering cation resins (e.g., cholestyramine, colestipol and colesevelam).
-These resins bind bile salts by ionic interaction with the bile salts that are negatively charged.
- In extreme circumstances an ileal exclusion operation can also interrupt the enterohepatic circulation.
- Both approaches block the reabsorption of bile acids, and initiate a favorable chain of events.
1) The reduced recycling of bile salts lowers the liver concentration and thereby feedback repression that is normally exerted by bile acids on the 7 alpha hydroxylase is lost.
2) Increased amounts of the hydroxylase mean that the conversion of cholesterol to bile acids is greatly enhanced in an effort to maintain the pool of bile acids.
3) Because the concentration of cholesterol in the liver is lower, LDL receptors in the liver increase.
4) The elevation in LDL receptors in the cell membrane leads to an increased hepatic uptake of LDL with consequent lowering of plasma cholesterol.
- One detriment to using these resins is that such treatment increases blood triacylglycerol concentration.
- A more common consequence of taking this medication is a feeling of abdominal fullness, which in turn has the added benefit of potentially lowering food intake.
Therapies for Treating Hypercholesterolemia - Nicotinic Acid
- This medication, also known as niacin or vitamin B3, is one of the water-soluble vitamins.
- As discussed in the Musculoskeletal System block, niacin serves as a precursor for redox components including NAD+ and NADH, which are essential in energy metabolism.
- Niacin has another unique function in that therapeutically it increases the blood concentration of HDL and lowers LDL.
- Niacin in combination with simvastatin may slow the progression of heart disease including reducing the risk of heart attack.
- Niacin lowers lipids by directly inhibiting diacylglycerol acyltransferase-2, a key enzyme for synthesis of triacylglycerol.
- In turn this leads to decreased secretion of VLDL by liver and therefore decreased formation of LDL in the circulation.
- The positive effect of niacin in increasing HDL stems from niacin decreasing the catabolism of apolipoprotein A-1, a key component of HDL particles. Consequently the half-life of HDL is increased.
- The most significant side effect of high dose niacin is flushing.
-Flushing results from the stimulation of production of certain prostaglandins that in turn cause cutaneous vasodilation.
- Additional effects may include headache, dizziness, and blurred vision.
- Long-term use has been linked to liver damage. Hence patient liver function (damage) must be closely monitored by analysis of blood concentrations of ALT and AST.
Therapies for Treating Hypercholesterolemia - Fibrates
- These medications are most effective at lowering triacylglycerol and improving HDL with little effect on LDL.
- This effect on circulating triacylglycerol stems from the fibrate effect on liver VLDL production and by increasing triacylglycerol clearance from the blood.
- Fibrates are often prescribed in combination with statins.
- The mechanism of fibrate action is not understood.
Therapies for Treating Hypercholesterolemia - Decreasing Intestinal Cholesterol Absorption
- Ezetimibe (Zetia) lowers the intestinal absorption of dietary cholesterol.
- It may be prescribed in combination with statins (a combination preparation is available) or used alone if taking statins produces significant side effects (see above).
- In high-risk patients with acute coronary syndrome, ezetimibe in combination with a statin more effectively lowers the risk of cardiovascular events than with statin therapy alone.
- Ezetimibe acts at the level of the intestinal brush border where it binds to the Niemann-Pick CLike (NPCL1) protein on the epithelial cells.
-NPCL1 is the mediator of cholesterol uptake from the lumen of the intestine.
- The decreased absorption of cholesterol in turn leads to less cholesterol in the liver causing increased uptake of LDL-cholesterol from the blood.
- Plant sterols, like ezetimibe, reduce intestinal cholesterol absorption, albeit by a different mechanism.
-The effects of ezetimibe and plant sterols are not additive, and plant sterols alone are less effective than ezetimibe.
- The most common adverse effects of ezetimibe include headaches and/or diarrhea.
- Some patients may exhibit myalgia and some liver effects.
- Hence, as with many cholesterol-lowering medications, patients should be tested for evidence of liver damage (AST/ALT plasma concentration) as well as plasma muscle creatine kinase (CK).
Lipoproteins
- Circulating
- Apolipoproteins
Circulating Lipoproteins Composition
- Circulating lipoproteins are spherical multi-component particles of protein and lipid held together by non-covalent (largely hydrophobic) forces (see LDL).
- Analogous to micelles, the core of lipoproteins is hydrophobic, consisting of non-polar lipids (triacylglycerol and cholesterol esters).
- The outer layer consists of a detergent coat made up of a phospholipid monolayer and free cholesterol that facilitates solubility in aqueous blood.
Apolipoprotein Composition
•Apolipoproteins are specific lipid-binding proteins that attach to the surface of the particle, to stabilize it and to function as ligands for cell membrane receptors or as enzyme activators.
General Lipoprotein Composition
- Lipoprotein particles undergo continuous metabolic processing/remodeling, so they have variable properties and compositions, but the main lipid components are triacylglycerols, cholesterol esters and phospholipids.
- Other lipids carried by lipoproteins include free cholesterol, fat-soluble vitamins and trace amounts of free fatty acids.
Unlike most membranes, the one around a lipoprotein is a monolayer. The outer surface is coated with apoproteins and the core is comprised of cholesterol ester and triacylglycerol in proportions that vary with each type of lipoprotein
Major Lipoproteins of the Endogenous System
Arranged by Density:
- very low density lipoproteins (VLDL)
- intermediate density lipoproteins (IDL)
- low density lipoproteins (LDL)
- high density lipoproteins (HDL)
Arranged by Charge:
- HDLs = alpha -lipoproteins
- LDLs = beta -lipoproteins
- VLDLs = pre-beta lipoproteins (intermediate between alpha and beta mobility)
Apolipoprotein
•Each lipoprotein has a characteristic apolipoprotein composition. Beyond the physical surface stabilization of lipoprotein particles, apolipoproteins have 3 main functions:
1) intracellular recognition for exocytosis of the nascent particle after synthesis
2) activation of lipid-processing enzymes in the bloodstream
3) binding to cell surface receptors for endocytosis and clearance.
VLDL
- VLDL, a triacylglycerol-rich lipoprotein, is produced and secreted by the liver.
- The triacylglycerol is formed from free fatty acids that are either mobilized from adipose cells or synthesized in liver from acetyl CoA derived from nonlipid precursors, primarily from glucose.
- A major function of this lipoprotein is to transport endogenously synthesized triacylglycerol from the liver to extrahepatic tissues.
- VLDL secreted into the circulation also contains apolipoprotein B100 that is synthesized in liver.
- The primary role of apo B100 in this process is to aid in the proper assembly and export of nascent VLDL.
- The only protein contained in the nascent form of VLDL is apo B100.
- Chylomicrons are assembled using apo B48 in a similar manner.
- Apo B48 is a truncated version of apo B100 lacking 52% of the linear structure.
- The additional portion of apo B100 accounts for its ability to bind to the LDL receptor.
- Release of VLDL by liver is augmented by any condition that results in increased flux of free fatty acids to the liver in the absence of their conversion to ketone bodies.
- Obesity, increased caloric intake, chronic ingestion of ethanol and estrogens stimulate release of VLDL and are important factors in hypertriglyceridemia.
- The second major function of VLDL is to provide liver-generated cholesterol esters for LDL that carries the cholesterol to peripheral cells, and back to the liver.
- After secretion from the liver, VLDL matures by acquiring apolipoproteins CII and E in the plasma from HDL particles.
-Liver cells synthesize and export the apo CII and E proteins to be picked up by HDL particles.
- Mature VLDL converts to IDL and then LDL particles following hydrolysis of triacylglycerol to three fatty acids and the glycerol backbone. T
- Triacylglycerols in VLDL (also chylomicrons) undergo lipolysis catalyzed by lipoprotein lipase (LPL).
- LPL lies on endothelial cell surface of capillary walls and hydrolyzes triacylglycerols to release fatty acids taken up and used primarily by adipose and muscle cells.
- LPL is primarily associated with heart, skeletal muscle, adipose and mammary cells. In muscle, released fatty acids are oxidized for energy.
- In adipose cells fatty acids are re-esterified for storage as triacylglycerols.
- LPL is activated by apolipoprotein CII, bound to phospholipids on the VLDL and chylomicrons.
- In the fed state, insulin increases activity of LPL while in starvation the activity declines.
IDL
- After repeated rounds of action by LPL, VLDLs decrease in surface area as their triacylglycerols are progressively hydrolyzed until they are reduced to cholesterol ester-enriched IDL (intermediate density lipoprotein) and ultimately to LDL.
- Approximately 50% of the IDL particles are taken up by the liver after binding to the apo E receptor with the remainder converted to LDLs.
- The half-life of IDL particles is less than 30 minutes.
- The apo CII and apo E associated with the IDLs is released back to the HDL particles.
- Genetic defects in the apo E ligand or its receptor elicit Type III hyperlipidemia, in which IDL, as well as chylomicron remnants and HDL, are elevated.
LDL
- Cholesterol ester in LDL may originate from cholesterol directly synthesized by the liver (endogenous pathway), or indirectly from the diet via the clearance of chylomicron remnants by the liver (exogenous pathway).
- The primary function of LDL is to provide cholesterol to peripheral tissues.
- LDL is taken up and removed from the circulation by cells having surface LDL receptors that bind apo B100.
- Normally, more than half of the LDL binds to receptors on liver hepatocytes.
- The balance of the LDL associates with receptors on peripheral cells.
LDL Uptake
- LDL uptake is a model for receptor-mediated endocytosis of lipoproteins.
- Most dividing cells have LDL receptors.
- These are transmembrane glycoproteins that bind apo B100.
- LDL receptors are clustered in pits on cell membranes. The intracellular side of these pits is coated with clathrin.
- After binding, the coated pit closes and LDL is internalized by endocytosis.
- Endocytosed vesicles containing LDL bound to its receptor rapidly lose clathrin and fuse with a second vesicle that has an internal pH of about 5.0, to form a sorting endosome.
- The acidity of the sorting endosome causes the LDL particles to dissociate from the receptors.
- The freed LDL receptors recycle to the plasma membrane.
- The LDL particles with its cholesterol ester (CE) accumulate inside a transport vesicle.
- After the transport vesicle fuses with lysosomes, a late endosome forms.
- In the late endosome, apo B100 is hydrolyzed to its component amino acids and cholesterol esters are de-esterified by acid cholesterol ester hydrolase (ACEH) to form free cholesterol and fatty acids.
- NPC-1 protein then mediates the translocation of cholesterol into the free (unesterified) cholesterol pool in the Golgi apparatus, which functions as a “switching yard” for cholesterol disposition.
- From the Golgi, cholesterol may be esterified by ACAT (acyl CoA:cholesterol acyl transfer) for storage in cytoplasmic droplets, metabolized to steroid hormones or cholesterol, or converted to bile acids (liver only).
- LDL receptor binding sites are nearly saturated under most circumstances.
-Hence the capacity of the LDL receptors may be easily exceeded either because of a reduction in receptor amount due to a genetic defect or because of elevated circulating LDL due to excessive cholesterol intake and/or synthesis.
- Lipoprotein disorders in which LDL receptors, or their capacity to bind the apo B100 ligand, are defective, result in an increased concentration of cholesterol in LDL remaining in circulation, causing hypercholesterolemia and atherosclerosis.
- Additionally, PCSK9 (proprotein convertase subtilisin/kexin type 9) binds to the LDL receptor thereby blocking the uptake of LDL particles and thereby increasing the concentration of circulating LDL particles.
-This scenario, plus the potential of LDL to become oxidized to an atherogenic form, has caused it to be dubbed the “bad” cholesterol carrier.
•The circulating concentration of LDL cholesterol may be reduced by increasing the number of LDL receptors found in the plasma membrane when the intracellular concentration is low.
Oxidized LDL
- Oxidized LDL is more atherogenic than native LDL.
- Apo B-containing LDL particles are subject to oxidative damage by reactive oxygen species (e.g., radicals or peroxides).
- Oxidation and the production of reactive oxygen species results from normal metabolism, but damage can be minimized with antioxidants in foods (e.g., prunes, raisins, blueberries, garlic, etc.) and with antioxidant vitamin and mineral supplements (e.g., vitamins C and E, carotenoids, selenium, etc.).
- The “oxidized (modified) LDL” is taken up via scavenger receptors on macrophages (scavenger cells) ten times more rapidly than native LDL.
- The cholesterol-laden macrophages release chemicals (cytokines) that promote inflammation, cell proliferation and aggregation.
- These cholesteryl ester-laden macrophages invade the intimal smooth muscle layer of blood vessels and become “foam cells” that in turn oxidize more LDL.
- Oxidized LDL particles deposited in atherogenic plaques attract more macrophages, initiating a vicious cycle, with the ensuing damage to the artery being difficult to reverse.
- The foam cells lead to the production of “fatty streaks”, which are precursors of fibrous plaque.
- Platelets may aggregate at the site of the arterial wall lesion becoming raised and developing into an atheroma.
-An atheroma is defined as “degeneration of the walls of arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation and a risk of thrombosis (local blood clotting)”.
HDL
- HDL has essentially the opposite function of LDL: it removes cholesterol from tissues.
- HDL is synthesized in liver and intestine, which secrete the pre-HDL into plasma as a discoidal particle (nascent HDL) that contains only apo A1 and phospholipds.
- A phospholipid transfer protein facilitates the incorporation of phospholipids into HDL.
- Mature HDL contains lecithin, cholesterol ester, LCAT, and apolipoproteins A1, CII, and E.
- Circulating HDL acquires cholesterol by extracting it from peripheral cells.
- HDL particles dock with membrane scavenger receptors via the apo A1.
- Cholesterol removal by HDL is facilitated by cholesterol efflux regulatory protein (CERP), an ATP-binding cassette protein transporter.
- CERP is activated by apo A1, which also flips free cholesterol and lecithin to the outer layer of cell membranes.
- CERP delivers free cholesterol and lecithin as substrates for lecithin:cholesterol acyl transferase (LCAT), which is activated by apo A1 on HDL.
- Cholesterol esters, the product of LCAT catalysis, move to the core of nascent HDL.
- The entire process of LCAT extraction of cell cholesterol and incorporation into HDL for liver clearance is called “reverse cholesterol transport”.
- A rare disease associated with a defect in CERP is Tangier diseases.
- The mature HDL particles are taken up by the liver following binding to apo E receptors.
- The liver is the only organ capable of disposing of significant quantities of cholesterol, either via excretion into the bile or by metabolism to bile acids, both of which are lost to some degree in the feces.
- HDL therefore functions as a cholesterol scavenger, facilitating the transport of cholesterol to the liver for conversion to bile acids and eventual elimination.
- It is this cholesterol-removing property that makes HDL the “good” cholesterol carrier.
- Of course another major function of HDL is that it serves as a repository for apolipoproteins,
-A1, CII and E. Transfer of apo CII is required for the metabolism of VLDL (and chylomicrons), and apo E is crucial for clearance by liver of IDLs and HDLs, as well as remnants from chylomicrons.
•Therefore, HDL contributes to both the exogenous and endogenous pathways of lipid transport.
