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24 Cards in this Set

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  • Back
Discuss lipid transport in the blood by lipoproteins and albumin
High Protein = High Density
High TAG = Low Density

VLDLs & Chylomicrons transport TAG
LDLs transport cholesterol and cholesteryl esters
HDLs label the othes for uptake by liver or clean them directly
Describe the location and function of LPLase
1. Heart
2. Muscle
3. Adipose Tissue

Hydrolyze TAG from lipoproteins, ↓ size, ↑ density
Discuss chylomicron metabolism starting from formation to its uptake into the liver
1. Released from intestines in the blood via lymph
2. Metabolised (split into FA & glycerol) by LPLase (bound to capillary endothelial cells)
3. Fatty acids taken up by target cells or bound to albumin
4. Remnants taken removed by the liver
Discuss the transport of dietary triacylglycerols from the intestine to the peripheral tissues. (5 steps)
Dietary lipid is digested in the enterocytes of the duodenum
1. Chylomicron is exocytosed into the blood stream
2. apo C-11 and apo E are transferred to the chylomicron from an HDL, joining te apoB-48 label created in the enterocyte
3. Extracellular lipoprotein lipase, activated by apo C-11, degrades the TG inside the chylomicron, releasing free fatty acids and glycerol for extrahepatic tissues.
4. apo C-11 is returned to an HDL for reuse as the chylomicron is completely degraded
5. apo E on the remnants binds to receptors on the liver where they are endocytosed and their components recycled.
Describe the conversion of IDLs to LDLs performed by hepatic TAG lipase
IDLs are broken down to TAG and cholesteryl esters in the liver by Hepatic TAG lipase (HTGL). The liver can also remove them from circulation
Discuss the uptake tissues of LDL into the liver and extra-hepatic tissues by receptor mediated endocytosis
LDL contains free cholesterol and cholesteryl esters in a protein package with the apoB-100 marker. Once recognized, these lipoproteins are incorporated through receptor mediated endocytosis.

Other than the gonads and adrenal cortex, tissue affinity for apoB-100 is much lower than for apo E. They take up the majority of the LDLs for steroid hormone synthesis. Once in the cell:
1. An endosome fuses with the LPL
2. Lysosomal enzymes degrade it into free cholesterol, NEFAs and amino acids
3. The cholesterol is used for steroid and membrane synthesis and can also be re-esterfied by acyl-CoA-cholesterol acyltransferase (ACAT) & stored.
Describe the regulation of LDL-receptor synthesis
Elevated intracellular cholesterol levels inhibit HMG-CoA reductase (down-regulate re-esterification) as well as reducing LDL-receptor gene expression.

In contrast, low levels increase LDL-recptor gene expression.
Outline the receptor-mediated process involving LDL and LRP receptors
LDL receptors proteins (LRPs) are found in clathrin coated pits and are able to recognize either apoE and apoB-100 markers. As they are brought into the cell they are packaged in clathrin-coated vessicles.
Discuss the functions and effects of deficiencies of apo B-48
apo B-48: unique to chylomicrons from the small intestine. apo B-48 returns to the liver as part of the chylomicron remnant. Defiency leads to abetalipoproteinemia and fat malabsorption as CMs, VLDLs and LDLs can not be digested.
Describe the reverse cholesterol transport performed by HDL
1. Pre-beta HDLs are made in the liver or intestines
2. Pre-beta HDL picks up cholesterol from the membranes of extrahepatic cells
3. Cholesterol acyltransferase (Lecithin or LCAT) esterizes HDL cholesterol by a process called Entrapment. This makes completely hydrophobic cholesteryl esters and moves them into the center of the HDL.
4. Cholesteryl ester transferase protein (CETP) trades esterified cholesterol from HDL3s (activated) for TAG in VLDLs, reducing them to IDLs and LDLs.
5. The HDL3, now an HDL2, goes to liver where it encounters either a hepatic lipase (HGTL) which removes the TAG allowing it to one again collect cholesterol, or an HDL receptor which removes it from circulation.
Describe the synthesis, location and action of lecithin: cholesterol acyltransferase (LCAT)

- I think this answer is wrong and am meeting with Dr. Williams to discuss it.
Lecithin or cholesterol acyltransferase (LCAT) is synthesized in the liver but works in HDLs. It reduces the level of free cholesterol, regulates composition of plasma lipoprotens & indirectly cholesterol content of membranes.

Alternately, ACAT synthesizes the following reaction on the cytosolic face of the ER:
acyl-CoA + cholesterol ↹ CoA + cholesterol ester

LCAT activation requires interaction with apoA-1, synthesized by enterocytes and hepatocytes.
Describe the biochemical basis of atherosclerosis in Tangier disease and name the defective transporter
• Rare autosomal disorder causing low [HDL] in plasma.
• Cholesterol accumulates in extrahepatic tissues, particularly the reticuloendothelial system.
• Engorged macrophages accumulate in lymphoid tissues eg. tonsils.
• ABC1 transporter is involved in the removal of membrane cholesterol by HDL particles (cholesterol-efflux regulatory protein).
• Nascent apo A-1 do not acquire cholesterol.
• Plasma LDL levels 1/3 normal, because the transfer of cholesterol esters from HDLs to VLDLs is not possible.
Describe the function of cholesterol ester transfer protein (CETP)
It is an enzyme that exchanges cholesterol esters from an HDL to a VLDL or chylomicron in exchange for TAG. Deficiency in CETP causes increased HDL cholesterol and low HDL TAG levels. These patients are resistant to atherosclerosis however.
Describe the delivery of cholesterol esters to the liver by HDL2 via SRB-1 and using the phospholipase activy of hepatic lipase
The receptor SRB-1 (scavenger receptor class B1) present on the liver cells’ plasma membranes mediates most of the liver’s uptake of cholesteryl esters from HD. Once in the liver, the cholesteryl esters are converted to cholesterol and enter the general pool. Therefore, the liver can eliminate cholesterol from the body by secreting unesterified cholesterol into the bile or by converting cholesterol to bile acids.
Uptake of HDL2 is mediated by hepatic lipase. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of HDL2 in women.
Explain how cholesterol esters from HDL can reach the liver via IDL and LDL
Cholesterol esters are carried to the liver inside the IDL or LDL that traded HDL for them. They are then recycled.
Explain how oxidized LDL particles are formed and how they are involved in foam cell development and alterosclerosis
1. Injury to blood vessel endothelium, partially caused by oxidated LDLs, attract monocytes which adhere to the endothelial cells and move to the subendothelium (intima) and are transformed to macrophages.
2. Macrophages consume excess modified lipoprotein, becoming foam cells
3. Foam cells accumulate and release growth factors that stimulate the migration of smooth muscle cells. They proliferate, produce collagen and take up lipid, becoming foam cells themselves.
4. A bleb is formed on the wall of the lumen which constricts flow and encourages more growth as the lower pressure allows more accumulation of debris.
Discuss the significance of Lp(a) and LDL-B
Lp(a) is similar to an LDL with apoA attached to its apoB. They are part of a different pathway from LDLs but still contribute to atherolosclerosis.

LDL-B has smaller particles than other LDLs, a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles (Pattern A). This is because the smaller particles are more easily able to penetrate the endothelium.
Describe Type I, Type IIa, IIb, III, IV and V hyperlipidemias (causes, lipid profile abnormalities, biochemical basis of clinical manifestations)
Type I - Familial LPLase deficiency: a) LPLase deficiency, b) abnormal LPLase, c) apoC-II deficiency. Leads to ↑TAG/Chylomicrons
Type IIa - Familial Hypercholesterolaemia (FH): ↑LDLs & - VLDLs caused by defective LDL receptors secondary to 4 different mutations.
Type IIb - Familial Combined Hyperlipidemia: ↑LDL & hypertriglyceridaemia (↑VLDL); ↓HDL. Biochemical defect is not understood.
Type III - Hyperlipidaemia: apoE abnormalities interfere with hepatic chylomicron remnant and VLDL removal. ↑TAG & IDLs
Type IV - Familial Hypertriglyceridaemia: Overproduction of VLDL. ↑TAG
Type V - Similar to Type I: Familial LPLase deficiency but leads to ↑VLDL & chyolmicrons. Biochemical basis is unknown.
Describe the biochemical basis for the use of statins and bile acid sequestering agents in hypercholesterolemia
Statins competitively inhibits HMG-CoA reductase, the rate limiting step of cholesterol biosynthesis. It facilitates the conversion of HMG-CoA to Mevalonate which is eventually turned into cholesterol. This also disrupts synthesis of Farnesyl-pyrophosphate however, a precursor for CoQ and dolichol.

Bile acid sequestering agents coagulate bile, preventing it's absorption in the inestines and leading to it's excretion from the body. This forces the liver to synthsise more bile from its cholesterol stores.
Discuss the functions and effects of deficiencies of apo B-100
Found in lipoproteins originating from the liver (VLDL, IDL, LDL). Directly related to cardiovascular disease secondary to athelesclerosis.

1. Too many LDLs compete for receptors and stay longer in blood
2. With a longer half-life, they have a better chance of being oxidized or glycosylated.
3. Modified LDLs are picked up by macrophages, become foam cells.
4. Foam cells enter epithelial lesions in blood vessels where they build up
5. These build-ups narrow the lumen of the vessel, causing athelerosclorosis.
Discuss the functions and effects of deficiencies of apo C-II
A component of very low density lipoproteins and chylomicrons, activating lipoprotein lipase (LPLase) in capillaries.

Mutations in this gene cause hyperlipoproteinemia type IB, characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis.
Discuss the functions and effects of deficiencies of apo E
Found on chylomicrons and IDLs binding to receptors on liver and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Deficiencies or mutations are implicated in atherolosclerosis, cardiovascular disease, immune system depression and hyperlipoproteinemia.
Discuss the functions and effects of deficiencies of apo A-1
Major component of HDLs. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly transferred to HDL. Promotes cholesterol efflux from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. It may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.