(9/14/10) - Lipoprotein Metabolism



'''1. List the main organs that export lipids into the circulation. '''

Liver (fed--VLDL), Small intestine (fed), adipose tissue (fasting).

'''2. Describe how it is possible to transport lipids at levels exceeding their solubility in circulation and how it relates to the physical properties of the transport vehicle. '''

Proteins such as serum albumin and lipoproteins function to keep lipids soluble as they are transported throughout the circulation. These 'vehicles' are amphipathic—they have a hydrophilic exterior, but a hydophobic interior. It is not a perfect system, leading to a slow deposit of lipids in the blood vessels, resulting in atherosclerosis.

'''3. List the main classes of lipoproteins and describe their composition. Relate their composition to their mode of synthesis and function. '''

Apoproteins play a structural role, coenzymes or activators of enzymes that metabolize the lipoproteins, and recognition sites for the cell surface receptors.

'''4. Describe how lipoprotein compositions change during their passage through the body’s circulatory system and which enzymes and proteins act as important modifiers. '''

When chylomicrons are first dumped into the lymphatic and circulatory system, they are referred to as nascent (newborn) particles. These chylomicrons acquire two apoproteins from HDL (CII and E) to become a mature chylomicron. VLDLs undergo a similar modification and transition to IDL and LDLs while in the bloodstream. TAGs from VLDLs are exchanged for cholesteryl esters with HDLs.

'''5. Describe how lipoproteins/their contents are removed from the circulation with special emphasis on the role of receptors. List those receptor subtypes that have pathophysiological importance and describe why. '''

Chylomicrons and VLDLs pick up ApoCII from HDLs upon entering the circulation. This protein acts as a cofactor for the receptor/enzyme LPL (lipoprotein lipase). This enzyme digests TAG molecules of chylomicrons and VLDL into fatty acids and glycerol. The fatty acids are then oxidized or stored (if they are not immediately taken up, serum albumin transports them until uptake does occur). As the chylomicron moves through the blood, the TAGs get digested and the particle decreases in size and increases in density. ApoCII are also returned to HDLs, and the remaining remnants are taken up by the liver via receptor mediated endocytosis. These lipoprotein receptors recognize ApoE.

VLDLs are digested in a similar fashion as chylomicrons, and they also decrease in size and become denser. The CII and E apoproteins are returned to HDL, but the particles retain B-100. Triacylglycerides are also transferred to HDL, which in turn transfers cholesteryl esters to VLDL. This ultimately converts the VLDL molecule to LDL (the IDL is a transition molecule in this process). IDLs can be taken up by cells through receptor-mediated endocytosis (using ApoE as the ligand), or additional TAGs can be removed from IDL by HTGL on hepatocytes. LDLs are also taken up through receptor-mediated endocytosis (using ApoB-100 as the ligand). Note that the LDL receptors are also called ApoE/ApoB-100 receptors, so they play a role in the uptake of all the lipoprotein molecules taken up by endocytosis, but bond preferentially to ApoE.

The HDL matures by accumulating phospholipids and cholesterol (cholesterol esters fill the core). Lecithin-cholesterol acyl transferase (LCAT) takes excess cholesterol in the chylomicrons and VLDL (and cell surfaces) and moves it to HDL and there it is converted to the ester. LCAT is present in plasma and requires apoA1 (present in HDL) for activity. The excess cholesterol esters move back into the shrinking remnant (VLDL and chylomicrons) with the help of cholesterol ester transfer protein (CETP).

Familial lipoprotein lipase deficiency (type I hyperlipoproteinemia) is a result of a deficiency of LPL or ApoCII, which results in an increased plasma level of chylomicrons (and thus TAGs). Familial type III hyperlipoproteinemia (familial dysbetalipproteinemia or broad beta disease) is the result of two genes for the ApoE2 lipoprotein, which does not bind well to the receptors, resulting in a deficiency in the clearance of chylomicron remnants and IDLs. ApoE4 also confers an increased susceptibility to late-onset Alzheimer disease.

'''6. Recognize the pathophysiology of Familial Hypercholesterolemia (FHC) and describe the common underlying disease mechanism. '''

A deficit of function LDL receptors causes a significant elevation of plasma LDL (and therefore plasma cholesterol), leading to premature atherosclerosis. Over 300 mutations have been found. FHC heterozygotes (1:500) take up LDL at half the normal rate. FHC homozygotes have serum cholesterol levels 500-800 mg/dL. LDL receptors recognize B-100 (not B-48) and apoprotein E. Since LDL only has a B-100 remaining on it, so it only has one chance to be taken up by the liver, via the LDL system. These people also overproduce LDL because they cannot take it up.

'''7. Outline the mechanisms and regulation of the intracellular cholesterol concentration including the role of relevant transcription factors, receptors and enzymes. '''

HMG CoA reductase is inhibited by high cholesterol, so de novo synthesis decreases. Synthesis of new LDL receptor protein is also reduced by decreasing the expression of the LDL receptor gene. This will limit further entry of LDL cholesterol into the cells. Cholesterol can also be stored by esterifying it by acyl CoA:cholesterol acyltransferase (ACAT), which transfers a fatty acid from a fatty acyl CoA to cholesterol. ACAT is enhanced in the presence of increased intracellular cholesterol.

8. Describe the process of reverse cholesterol transport and its integration into lipoprotein metabolism.

HDL picks up excess cholesterol from peripheral cells, converts it to a cholesterol ester (using Phosphatidylcholine cholesterol transferase (PCAT, or LCAT), the binding of the cholesterol-ester rich HDL to the liver, the selective transfer of the esters into the cells, and the release of lipid-depleted HDL.

'''9. Define dyslipidemia and atherosclerosis. '''

Dyslipidemia is a result of insulin resistance, which results in increased activity of hormone-sensitive lipase. The lipase breaks down TAG in adipose tissue and results in the release of free fatty acids and glycerol into the bloodstream. The liver takes up these fatty acids and converts them to TAGs and cholesterol. Excess of these are released as VLDLs into the bloodstream, which results in elevated serum TAGs, and a decrease in HDLs. Atherosclerosis is the narrowing of the blood vessels resulting from plaque formation. Plaque formation is a result of lipid deposits in the vessels from excess fatty acids circulating through the blood.

10. Predict the effects of specific enzyme/receptor deficiencies on the production of various lipoprotein species.

'''11. Explain the health risks associated with dyslipidemia and atherosclerosis. '''

In atherosclerosis, a ruptured plaque could result in infarction, or the plaque could simply grow large enough to occlude the blood vessel itself. Dyslipidemia has the potential to cause atherosclerosis.

12. List the main component processes of atherogenesis and briefly describe their relation to atherosclerotic plaque formation and rupture.

Endothelial dysfunction (damage allowing for fatty streak formation; healing over plaques), arterial deposition of lipids (form fatty streaks, foam cells), chronic low-grade inflammation (weaken the cap)

'''13. Explain the atherogenic potential of different lipoprotein species with special attention to the role of oxidative damage. '''

Oxidized LDL is the most atherogenic particle, as it is no longer recognized by the LDL receptor, but rather by macrophages. Once the macrophages ingest the LDL particles, they cannot break down the cholesterol, and turn into foam cells, which are deposited in fatty streaks or form atherosclerotic plaques. Lipoprotein (a) is an LDLbonded to apo (a) by a disulfide bond. Apo (a) resembles plasminogen, so Lp(a) can act as a competitive inhibitor for plasminogen activators, thus reducing the ability of the body to break down clots that may cause stroke or myocardial infarction.

'''14. List and briefly describe common treatments used to control blood lipid levels. Explain the mechanism by which they act, if known. '''