Lipoproteins amp their Metabolism Functions of Lipoproteins General Characteristics of Lipoproteins The lipoprotein molecules have a polar periphery made of proteins polar heads of phospholipids and cholesterol The inner core consists of the hydrophobic ID: 919194
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Slide1
Dr. ali al-bayati
Lec.
5
Lipoproteins &
their Metabolism
Slide2Slide3Functions
of Lipoproteins
Slide4General Characteristics of
LipoproteinsThe lipoprotein molecules have a polar periphery made of proteins, polar heads of phospholipids and cholesterol. The inner core consists of the hydrophobic TAGs, cholesterol esters and tails of phospholipids. The apoproteins also increase the solubility of lipids.
Slide5Slide6Slide7Slide8Slide9Slide10The
protein part of lipoprotein is called apolipoprotein (apo-Lp) or apoprotein. All apoproteins are mainly synthesized in liver; but small quantities are produced from almost all organs. Intestinal cells produce small quantities of apo-A. Apo-lipoproteins
Functions of Apolipoproteins
Slide11Some of the apolipoproteins are required as essential structural components of the particles and cannot be removed
others are transferred freely between lipoproteins. Exchangeable apolipoproteins have regulatory roles; for example, apolipoprotein CII reversibly associates with VLDL particles and promotes their interaction with lipoprotein lipase.
Functions of Apolipoproteins; continue
Slide12Slide13Chylomicrons
are formed in the intestinal mucosal cells, and secreted into the lacteals of lymphatic system. They are rich in triglyceride.When the chylomicrons are synthesized by the intestinal mucosa, they contain only apo-B-48 and apo-A but apo-C and apo-E are added from HDL in blood during transport
Chylomicrons
Slide14Metabolism of Chylomicrons
Main sites of metabolism of chylomicrons are adipose tissue and skeletal muscle. The half-life of chylomicrons in blood is about 1 hour.The enzyme lipoprotein lipase (LpL) is located at the endothelial layer of capillaries of adipose tissue, muscles and heart; but not in liver. Apo C-II present in the chylomicrons activates the LpL. The LpL hydrolyzes triglycerides present in chylomicrons into fatty acids and glycerol. Muscle or adipose tissue cells take up the liberated fatty acids.Lack
of C-II leads to decreased activity of LpL and consequent accumulation of chylomicrons and VLDL in blood. Insulin increases LpL activity.
Liver Takes up Chylomicron Remnants; As the TAG content is progressively decreased, the chylomicrons shrink in size. These remnants containing apo B-48 and apo E are taken up by hepatic cells by receptor mediated endocytosis. Apo E binds the hepatic
receptors.
Slide15Slide16The VLDL carries triglycerols (endogenous triglycerols) from liver to peripheral tissues for energy needs.
They are synthesized in the liver from glycerol and fatty acids and incorporated into VLDL along with hepatic cholesterol, apo-B-100, C-II and E. Apo-B-100 is the major lipoprotein present in VLDL when it is secreted. ApoE and C-II are obtained from HDL in plasma.
Very Low Density Lipoproteins (VLDL)
Slide17The half-life of VLDL in serum is only 1 to 3 hours.
When they reach the peripheral tissues, apo C-II activates LpL which liberates fatty acids that are taken up by adipose tissue and muscle. The remnant is now designated as IDL (intermediate density lipoprotein) and contains less of TAG and more of cholesterol. The major fraction of IDL further loses triglyceride, so as to be converted to LDL (low density lipoprotein).
This
conversion of VLDL to IDL and then to LDL is referred to as lipoprotein cascade pathway.
Metabolism of VLDL
Slide18Low Density
Lipoproteins LDL(LDL) transports cholesterol from liver to peripheral tissues. The
only apoprotein present in LDL is apo B100.
Most LDL derived from VLDL, but a small part is directly released from liver.
The half-life of LDL in blood is about 2 days.The LDL is taken up by peripheral tissues by receptor mediated endocytosis
LDL receptors are located in specialized regions called
Clathrincoated
pits. Binding of LDL
to the receptor is
by apo
B100
When the apo B-100 binds to the apo-B-100 receptor, the receptor-LDL complex is internalized by endocytosis.
The endosome vesicle thus formed fuses with lysosomes. The receptor is recycled and returns to the cell surface. The LDL
particle are
hydrolyzed by lysosomal hydrolases, forming amino acids and free cholesterol. The free receptors can now return to the membrane surface to bind further LDL molecules.
Slide19~ 70
% of LDL is degraded in the liver, and the rest in extra-hepatic tissues. The free cholesterol is either incorporated into plasma membranes or esterified (by ACAT) and stored within the cell.
intracellular
cholesterol is regulated through cholesterol-induced suppression of LDL receptor synthesis and inhibition of cholesterol synthesis.
The increased level of intracellular cholesterol that results from LDL uptake activates ACAT, thereby allowing the storage of excess cholesterol within cells. This can lead to excess circulating levels of cholesterol. The excess cholesterol tends to be deposited within the arteries, leading to atherosclerosis.
Slide20High Density Lipoprotein
(HDL) Transfers cholesterol from peripheral tissues to the liver.
The major apoproteins in HDL are Apo A1, with some Apo A2, Apo C and Apo E
.
HDL serves as a plasma reservoir of Apo C and Apo E which can be transferred to VLDL and chylomicrons and back.
HDL particles are formed in blood by the addition of lipid to apo A-1, an apolipoprotein made by the liver and intestine and secreted into blood. [Note: HDLs are also formed within the liver and intestine.]
Slide21Functions of HDL
Apolipoprotein supply: apo C-II (to VLDL and chylomicrons activates of LPL) and apo E ( IDLs and chylomicron remnants for receptor mediated endocytosis).
Uptake of unesterified cholesterol;
Nascent HDLs are disc-shaped particles containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They take up cholesterol from non-hepatic (peripheral) tissues and return it to the liver as cholesteryl esters. [Note: HDL particles are excellent acceptors of unesterified cholesterol as a result of their high concentration of phospholipids, which are important solubilizes of cholesterol.
3. Esterification of cholesterol: When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme lecithin: cholesterol acyltransferase. This enzyme is synthesized and secreted by the liver. Lecithin is a component of phospholipid bilayer of the HDL disc.
Slide22Reverse
cholesterol transport: The selective transfer of cholesterol from peripheral cells to HDL, from HDL to the liver for bile acid synthesis or disposal via the bile, and to steroidogenic cells for hormone synthesis, is a key component of cholesterol homeostasis. This process of reverse cholesterol transport is, in part, the basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis and for HDL’s designation as the “good” cholesterol carrier.
[Note: Exercise and estrogen raise HDL levels.] Reverse cholesterol transport involves efflux of cholesterol from peripheral cells to HDL, esterification of the cholesterol by LCAT,
Slide23Hyperlipoproteinemia;A group of disorders characterized by increased plasma lipoproteins. They can be classified into 5 types, each of which may be familial or acquired.
1) Type I, Hyperlipoproteinemia;It is due to deficiency of lipoprotein lipase enzyme. Characterized by increased plasma chylomicrons and somewhat VLDL, but LDL and HDL are reduced. There is marked increase in plasma triacylglycerols & some increase in plasma cholesterol may occur. The plasma is turbid.2) Type II, Hyperbetalipoproteinnemia;It is characterized by increased plasma LDL. The familial type is caused by reduced LDL metabolism due to defective LDL receptors, the Apo B100 is not recognizing in by LDL receptors. There is marked increase in plasma cholesterol (familial hypercholesterolemia). Plasma is clear and the acquired type occurs in hypothyroidism.3) Type III, Dysbetalipoproteinemia
The patients with this type are characterized by increased VLDL (IDL) & chylomicrons remnants. The plasma is turbid. There is hypercholesterolemia & hypertriacylglycerolemia, the familial type is caused by deficiency of enzymes required for removal of VLDL & LDL from circulation. As well as, defective apo E was recognized, necessary for uptake and metabolism of VLDL and chylomicron remnants by liver.
4) Type IV, Hyperprebetalipoproteinemia;It occurs due to imbalance between synthesis and clearance of VLDL from circulation. This type is Characterized by increased plasma VLDL, triacylglycerols & some increase in plasma cholesterol. The plasma is turbid. The familial type is due to increased formation of triacylglycerols from carbohydrates. The acquired type occurs in severe type II DM, obesity & alcoholism.
5) Type V Hyperchylomicronemia & HyperprebetalipoproteinemiaThe patient with this type is characterized by increased chylomicrons and VLDL which leads to increase triacylglycerols & somewhat cholesterol. The plasma is turbid. The cause of disease is unknown, but may be due to increase formation of apo- B. it is usually associated with obesity and glucose intolerance
1) Type I, Hyperlipoproteinemia;
It is due to deficiency of lipoprotein lipase enzyme. Characterized by increased plasma chylomicrons and somewhat VLDL, but LDL and HDL are reduced. There is marked increase in plasma triacylglycerols & some increase in plasma cholesterol may occur. The plasma is turbid.
2) Type II, Hyperbetalipoproteinnemia;
It is characterized by increased plasma LDL. The familial type is caused by reduced LDL metabolism due to defective LDL receptors, the Apo B100 is not recognizing in by LDL receptors. There is marked increase in plasma cholesterol (familial hypercholesterolemia). Plasma is clear and the acquired type occurs in hypothyroidism.
3) Type III, Dysbetalipoproteinemia
The patients with this type are characterized by increased VLDL (IDL) & chylomicrons remnants. The plasma is turbid. There is hypercholesterolemia & hypertriacylglycerolemia, the familial type is caused by deficiency of enzymes required for removal of VLDL & LDL from circulation. As well as, defective apo E was recognized, necessary for uptake and metabolism of VLDL and chylomicron remnants by liver.
4) Type IV, Hyperprebetalipoproteinemia;
It occurs due to imbalance between synthesis and clearance of VLDL from circulation. This type is Characterized by increased plasma VLDL, triacylglycerols & some increase in plasma cholesterol. The plasma is turbid. The familial type is due to increased formation of triacylglycerols from carbohydrates. The acquired type occurs in severe type II DM, obesity & alcoholism.
5) Type V Hyperchylomicronemia & Hyperprebetalipoproteinemia
The patient with this type is characterized by increased chylomicrons and VLDL which leads to increase triacylglycerols & somewhat cholesterol. The plasma is turbid. The cause of disease is unknown, but may be due to increase formation of apo- B. it is usually associated with obesity and glucose intolerance
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