- Formed in the liver with ApoB-100
- Get ApoC-II and ApoE from HDL
- Apo C-II activates lipoprotein lipase (LPL)
- Degrade TAG -long chain fatty acid go to tissue, glycerol taken up by liver
- Returning Apo C-II and ApoE to HDL
- Becoming LDL- convert TAG to cholesterol ester
- Taken up through binding of ApoB-100
3. VLDL. When dietary lipid intake is lower, the liver synthesizes fatty acids from glucose and packages them as triglycerides in Very Low Density Lipoproteins (VLDL). Nascent VLDL resembles chylomicrons, although VLDL lipoproteins don't carry as many triglycerides as chylomicrons do. VLDL can be 1/5 to 1/10 the size of chylomicrons. They are packaged with apolipoprotein ApoB100. The liver can recycle any lipids remaining from the chylomicron remnants by repackaging them, along with any newly synthesized triacylglycerol, into VLDL and sending them into the bloodstream. Alternatively, the liver can use the lipids from chylomicron remnants for energy or incorporate them into lipid bilayers as needed. After the nascent VLDL is in the bloodstream, HDL transfers other apoproteins, including ApoCII and ApoE, to VLDL. This allows activation of LPL and breakdown of triglycerides to fatty acids and glycerol just as occurs with chylomicrons.
Note: Accumulating evidence indicates that depending on the tissue. For example, insulin is known to activate LPL in adipocytes to decrease expression of muscle LPL. Muscle and myocardial LPL is instead LPL isozymes are regulated differently and its placement in the capillary endothelium. By contrast, insulin has been shown
activated by glucagon and adrenaline. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue, whereas after a meal, the opposite occurs. The mechanisms were not well known.
Fig. 5. LDL Reaction with cells and regulations [Campbell & Smith, Biochemistry Illustrated, p. 155, Fig. 12-11]
Binding of LDL to cell surface receptor via Apoprotein B-100
Digestion of LDL components by lysosomal enzymes
Release of cholesterol from lysosomes
Regulatory functions of cholesterol:
cholesterol inhibits HMG CoA Reductase enzyme cholesterol inhibits LDL receptor biosynthesis cholesterol activates ACAT (acyl CoA cholesterol acyltransferase)
Molecular Biology Fact:Both Apo-B100 and Apo-B48 are encoded by the same gene.
Intestinal cells have a deaminase which changes the RNA (by RNA editing) from a C to a U, thus changing the CAA (gln) to a UAA (stop). Therefore, Apo-B48 codes from only the first ~half of the transcript.
Liver cells do not have the deaminase, resulting in a longer transcript and protein. Apo-B100 is about twice as long as ApoB-48.
ApoE2, ApoE3, and ApoE4 are 3 common isoforms, plus other, rare variants. ApoE generally has an anti-atherogenic role through regulation of lipoprotein metabolism and transport. ApoE2 is most protective and ApoE3 is intermediate, but ApoE4 is associated with Alzheimer's disease, Atherosclerosis, Diabetes, etc. Ongoing active research is uncovering
- Apo E receptor or SRB-1 bring HDL into liver
- ApoA-1 activates PCAT
- PCAT (Phosphatidylcholine: cholesterol acyl transferase ) esterifies cholesterol to CE
- ApoA-1 mediates the whole process
- In blood stream there is exchange between VLDL and HDL
- ApoA1 synthesized by liver, processed through ABCA-1 (complicated, and not very well understood mechanisms) to become nascent HDL, shaped like pancake.
- PCAT reaction converts Cholesterol to C-ester, which is non-polar and moves to middle, causing the HDL to become ball-shaped.
- Exchanges of various phospholipids, TG, and CE take place.
- Finally, HDL either drives past Liver depositing cholesterol via hepatic lipase, or meeting a receptor on the liver and becoming incorporated.
Receptors include the apoE receptor, and more commonly, the scavenger receptor SRB-1.
Atherosclerosis, coronary heart disease (CHD), and coronary artery disease (CAD) all describe a complex, multifactorial genetic disorder closely associated with lipoproteins and cholesterol. Because of its complexity, involving a myriad of genetic disorders and environmental interactions, teasing out the "causes" in a specific case is difficult or impossible.
A hallmark of CHD is the presence of excess LDL in circulation. In order for LDL and HDL to function to deliver and take up cholesterol from the peripheral tissue, these lipoproteins must leave the bloodstream, enter the extracellular matrix (ECM) and find the target cells. One theory of disorder leading to CHD is the excess time these lipoproteins spend in the ECM. In other words, the best situation is where the 'time in' vs. 'time out' is equal and short. The longer time LDL spends within the ECM, the increased danger of oxidation reactions that result in oxidized LDL. Endothelial cells can consume the oxidized LDL, releasing cytokines and growth factors and triggering inflammatory events. The oxidation of LDL also attracts monocytes which follow LDL out of the blood stream into the ECM. These monocytes become macrophages, and engulf the oxidized LDL, becoming a foam cell. Foam cells release growth factors to cause proliferation of the smooth muscle in the blood vessel wall, and calcification of the growing plaque. Over time, the accumulation of foam cells with increased inflammation results in plaque formation (atheromas) on the intimal (inner) surface of the major arteries. The blood vessels become abnormal and constricted. Vessels lose their elasticity, there may be decreased blood flow, and there is increased possibility of clot formation.
Several genetic abnormalities will result in increased circulating LDL. An autosomal dominant disorder called Familial Hypercholesterolemia affects the synthesis and/or expression of LDL receptors on cell surfaces. Without these receptors, LDL levels and therefore cholesterol levels rise in the bloodstream. Heterozygous individuals have very high cholesterol levels and experience earlier than normal cardiac incidences before the age of 35. Homozygous individuals may have a myocardial infarction around age 5.
The central role of LDL in CHD has prompted further studies of LDL with the hope of learning how to predict who is at higher risk of CHD and to develop and use specific drugs targeted toward LDL. Two types of LDL have emerged from such studies—(i) small, dense LDL and (ii) LDL containing apoprotein (a), called Lipoprotein (a). When an individual has increased amounts of small, dense LDL or increased levels of Lipoprotein (a), they are at increased risk of CHD.
Plasma LDL profile is characterized on the basis of size and density into two patterns: large, buoyant LDL (pattern A) and small, dense LDL (pattern B). Small, dense LDL (sd-LDL) penetrates more readily into the subintimal spaces, binds more tightly to proteoglycans in the ECM, therefore remaining longer in the ECM, and these types LDL are oxidized more rapidly than the larger LDL particles. There is some evidence of genetic determination of LDL particle size, with those individuals who have a preponderance of sd-LDL being at higher risk for developing CHD.
Lipoprotein (a) [called "lipoprotein little a" to distinguish it from the apoprotein A found on, and distinguishing HDL] is LDL bound to carbohydrate-rich apoprotein (a). The presence and extent of apoprotein (a) in a particular individual is determined to a great extent by their genetic makeup, reflecting the relative expression of the apo(a) gene locus found on chromosome 6; however, other gene loci also influence apo(a) expression to a lesser extent. Apoprotein (a) has a high structural homology to plasminogen and other plasma coagulation proteins; both apo(a) and plasminogen contain a series of "kringle" motifs which enable binding to fibrinogen. [Figure here] However, apo(a) lacks the fibrinolytic enzymatic activity of plasmin. Because of this similarity in binding sites, apo(a) binds to fibrinogen, thereby inhibiting fibrinolysis. Lp(a) particles are susceptible to oxidative modification because they bind avidly to proteins in the ECM. They are also susceptible to scavenger receptor uptake while in the ECM, leading to intracellular cholesterol accumulation and foam cell formation, and contributing to atherogenesis.
Three of the following five:
- Abdominal adiposity - accumulation of fat
- Low HDL
- Fasting hyperglycemia
- Inflammatory signs
- "...An interplay of obesity, inflammation, diabetes and coronary artery disease."
Metabolic syndrome is a group of risk factors linked to overweight and obesity. These are for the most part clinical signs.
Abdominal adiposity—having an apple shape, excess fat around the middle.
These clinical manifestations likely reflect only the "tip of the iceberg"
Predictive power for coronary heart disease events and for new-onset diabetes
Thoughts about treatment:
o If global risk is 15-20%, and + Metabolic Syndrome, consider treating as if global risk is >20%. (CHD risk equivalent with LDL goal of <100 mg/dL)
o If global risk is 5-10%, and + Metabolic Syndrome, consider treating as if is high-risk primary prevention. (Global risk of 10-20%, LDL goal of <130 mg/dL)
[From: Haffner & Taegtmeyer (2003) Epidemic obesity and the metabolic syndrome. Circulation 108:1541-5]
Categories of genetic disorders that predispose to atherosclerosis
Thrombosis [See Hemostasis/Coagulation]
Fibrinolysis [See Hemostasis./Coagulation]
Oxidation/antioxidants [See Oxidants/Antioxidants]
Blood pressure/blood flow
Cells: Vascular smooth muscle cells, Blood cells (Platelets, White blood
cells), Endothelial cells lining blood vessels, etc.
Environmental and behavioral influences
Homocysteine (vitamin B12 and folate reduce homocysteine levels)
Hypertriglyceridemia (lose weight/avoid obesity; maintain good glycemic
control if diabetic, avoid high fat diet)
Hypertension (monitor & control, reduce salt intake, reduce stress, +/-
- Hypertriglyceridemia, due to high fat diet, diabetes, obesity, etc.
- Hypertension, due to stress levels, salt intake, meds, etc.
- Homocysteine levels —a separate risk indicator
- (decreased vitamin B12, vitamin B6, and/or folate)
Hyperlipidemias caused by one of these mechanisms:
Overconsumption of cholesterol or fats, or sugars. (physiological or
Inability to manufacture enough of or a particular kind of apoprotein (always genetic)
Defects in a type of apoprotein receptor (genetic)
Underutilization of certain lipoproteins (genetic)
Other causes (polygenic)
Physiological/environmental factors that could cause hyperlipidemias
Fibric acid/Fibrates—synthetic ligand of PPAR-a (peroxisome proliferator-activated receptor)
- Increased transcription of genes that degrade lipids
- Increased LPL expression, lowering VLDL
- Side effects: nausea, skin rash, gallstones, myopathy if combined w/statins
Niacin/ Nicotinic acid—reduces B-containing LPs, (mechanism unknown)
- increase HDL by blocking uptake by liver; decrease mobilization of TG, decrease VLDL and LDL synthesis
- Doses at 100x recommended dietary allowance (RDA)
- Side effects: flushing, nausea, glucose intolerance, gout
- Niacin causes decrease of liver TG synthesis, required for VLDL production.
- Useful in treatment of Type IIb hyperlipoproteinemia (both VLDL and LDL are elevated); also raises HDL levels