INTRODUCTION
LIPIDS topics are covered by 2 lecturers - Dr Win Mar Kyi (WMK) and myself (FAR). The topics have to fit into the number of slots allocated by the Phase I Committee, based on the Objectives submitted by the Department at Curriculum Reviews in the past. I only attended one Curriculum Review.
Lipid Metabolism is covered in 2 blocks in Phase 1 - Foundation and Endocrine. LIPIDS topics are covered by 2 lecturers - Dr Win Mar Kyi (WMK) and myself (FAR). The topics have to fit into the number of slots allocated by the Phase I Committee, based on the Objectives submitted by the Department at Curriculum Reviews in the past. I only attended one Curriculum Review.
- Lipid Structure & Function (FAR)
- Lipid Degradation (Fat Mobilisation); covered under Lipid Metabolism (FAR)
- Ketogenesis (WMK)
- Fatty Acid Synthesis; covered under Lipid Metabolism (FAR)
- Triglyceride & Phospholipid Biosynthesis; covered under Lipid Metabolism (FAR)
- Cholesterol (Steroid) Metabolism (FAR)
- Lipoprotein Metabolism (FAR)
- Integration of Metabolism
In Foundation Black, I covered one topic: Structure and Function of Lipids (1 Oct 2013).
In Endocrine Block, I covered 4 topics:
1. Lipid Metabolism (30 April 2014)
2. Regulation of Lipid Metabolism (30 April 2014)
3. Lipoprotein Metabolism (4 May 2014)
4. Cholesterol Metabolism (4 May 2014)
From an applied standpoint, lipids are important because pesticides are fat-soluble and can accumulate in adipose tissues of the body. This phenomenon is referred to as biological magnification.
http://www.rsc.org/education/eic/issues/2007May/PesticidesKeepingOneStepAhead.asp
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STRUCTURE AND FUNCTION OF LIPIDS 2013/14
Depending on how the lipids are grouped, the actual number of lipid classes may vary for different disciplines. In Chemistry, there are 9 LIPID CLASSES. However, we are only interested in a few classes which are of importance to Medicine.
- Simple fatty acids – saturated, unsaturated
- Mono-, di- and triglycerides (triacylglycerols)
- Glycerolphospholipid (phosphoglycerides) / phospholipids eg. lecithin (phosphatidyl choline)
- Sphingolipids
- Steroids & Sterols eg. cholesterol
- Prostaglandins
- Lipid-soluble Vitamins & Precursors
In Medicine, we are interested in only 4 LIPID CLASSES. The MAJOR TYPES OF LIPIDS are thus:
1. Triglycerides (neutral fats; comprise Fatty Acids and Glycerol)
2. Phospholipids
3. Sterols
4. Waxes (eg cerumen or ear wax)
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CHARACTERISTICS OF LIPIDS
Examples of LIPIDS are oils, fats, waxes, phospholipids, and steroids. LIPIDS have distinct characteristics:
Principle elements: C, H, & O
Some with P & N
Water-insoluble
Soluble in solvents
LIPIDS contain carbon (C), hydrogen (H), and oxygen (O).
Additionally, some lipids contain phosphorus (P) and nitrogen (N).
LIPIDS are complex molecules composed of carbon, hydrogen, and oxygen, +- phosphorus and nitrogen.
LIPIDS are generally water-insoluble and do not mix with water - they are immiscible with water and remain afloat (terapung). However, LIPIDS are soluble in other solvents, eg acetone, chloroform, hexane, petroleum ether (PE), kerosene, and others.
Most lipids are non-polar and are hydrophobic because they contain hydrocarbon chains. Hydrocarbon chains contain carbon and hydrogen.
If there are double or triple bonds in the hydrocarbon chain, the lipids are said to be “unsaturated”
Like carbohydrates, LIPIDS are energy-rich compounds made from carbon, hydrogen, and oxygen, whose ratio is much less than 1:2:1.
Lipids include fats, oils, and waxes.
Lipids are non polar hydrocarbons.
When sufficiently close together, weak but additive van der Waals forces hold them together.
They are not polymers in the strict sense, because they are not covalently bonded.
Vitamins are small molecules not synthesized by the body and must be acquired in the diet.
When sufficiently close together, weak but additive van der Waals forces hold them together.
They are not polymers in the strict sense, because they are not covalently bonded.
Vitamins are small molecules not synthesized by the body and must be acquired in the diet.
Waxes are highly non polar and impermeable to water.
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FATTY ACIDS
Fatty acids are non polar hydrocarbon with a polar carboxyl group.
Fatty acids are amphipathic: they have opposing chemical properties:
When the carboxyl group ionizes, it forms COO– (carboxyl group) and is strongly hydrophilic; the other end is hydrophobic and has CH3 (methyl group).
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FATTY ACID NUMBERING SYSTEM
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| http://drbonesshow.com/links/fats.html |
The first carbon after the carboxyl carbon is called the alpha-carbon and it is carbon number 2 of the fatty acid chain.
The beta-carbon is the second carbon after C=O and is located at carbon number 3 of the chain.
The last carbon atom in the chain is designated the omega-carbon, which is reflective of the fact that omega is the last letter of the Greek alphabet.
Look up the Greek alphabet.
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SATURATED FATTY ACIDS & FATS
Saturated fatty acids (SFA) have carbon-carbon single bonds.
Unsaturated fatty acids have carbon-carbon double bonds.
Saturated fats contain mainly SFA compared to unsaturated fatty acids.
Unsaturated fats contain mainly unsaturated fatty acids compared to SFA.
Fats with only carbon-carbon single bonds are called saturated fats.
Butter and coconut oil are examples of saturated fats (oils).
Example:
Stearic acid is an 18-carbon (18C) saturated fatty acid.
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Wikipedia
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ESSENTIAL FATTY ACIDS (EFA)
Different molecules of fat have different fatty acid molecules attached to glycerol.
Most of the fatty acids we need to build fats can be created or "synthesized" by the body.
There are 3 fatty acids that cannot be made in this way and therefore they must be included in our diet.
The 3 "essential" fatty acids are linoleic acid, linolenic acid and arachidonic acid.
They are all unsaturated fatty acids.
http://drbonesshow.com/links/fats.html
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COMPLEX VS SIMPLE LIPIDS
Glycerol is the main backbone upon which more complex lipids are built. Fatty acids are joined (esterified) to glycerol by ester bonds, to form triglycerides (also called triacylglycerols). Glycerol and fatty acids are simple lipid molecules. Triglycerides are considered as complex or simple lipid molecules, depending on who is doing the talking. In most textbooks, triglycerides are considered as complex lipid molecules. However, there are a few scientists who choose to look at triglycerides as simple molecules.
GLYCEROL
Glycerol contains 3 —OH groups, one at each carbon. (—OH is an alcohol functional group)
Glycerol is consumed in glycolysis.
Glycerol is sourced from the breakdown of triglycerides in adipose tissues (during fat mobilisation)
Glycerol is carried by albumin in blood and delivered to liver.
Fatty acids are non polar hydrocarbons with a polar carboxyl group at one end and a methyl group at the other end.
The fatty acid carboxylic group bond with the hydroxyl groups of glycerol in an ester linkage (ester bond).
The fatty hydrocarbon backbone consists solely of carbon atoms with hydrogen as side group.
Examples:
The minimum number of carbon atoms in a fatty acid backbone is 4 (in butyric acid).
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| Wikipedia |
Eicosapentaenoic acid (EPA) is a long fatty acid and has 20 carbon atoms in its backbone. It has 5 carbon double bonds, beginning at the 3rd omega carbon (n-3), counting from the methyl end). It belongs to the omega-3 class of fatty acids.
The maximum number of carbon atoms in a fatty acid backbone is 22 (in docosahexaenoic acid, DHA). It has 6 carbon double bonds beginning at the 3rd omega carbon (n-3).
TRIGLYCERIDES
Fats and oils are triglycerides (simple lipids), composed of fatty acids and glycerol.
One glycerol plus 3 fatty acids make a triglyceride:
A saturated triglyceride contains mostly saturated fatty acids.
An unsaturated triglyceride contains mostly unsaturated fatty acids.
Different fatty acids can bind to the same glycerol molecule, giving rise to a mixed triglyceride (mixed fat).
A mixed triglycerides contains both saturated and unsaturated fatty acids.
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SATURATED FATTY ACID (SFA) VS. UNSATURATED FATTY ACID (UFA)
A. Saturated Fatty Acids (SFA)
Saturated fatty acids (SFA) do not contain double bonds between carbons—they are saturated with H atoms.
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Examples:
(i) Butyric acid
(iii) Stearic acid
Stearic acid is a saturated fatty acid with 18 carbon atoms in its backbone and no carbon double bond (C18:0). It is found in coconut oil.
B. Unsaturated Fatty Acids (UFA)
Unsaturated fatty acids (UFA) contain some double bonds in the carbon backbone. They are grouped into 2 types, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA).
1. Monounsaturated fatty acids (MUFA) contain only one C=C double bond.
2. Polyunsaturated fatty acids (PUFA) contain more than one C=C double bonds.
Examples:
Butyric acid has 4 carbon atoms in its backbone and no carbon double bond (C4:0). It is the simplest saturated fatty acid. It is also the shortest saturated fatty acid. It is a main component of butter. Butter is solid at room temperature but melts easily at higher temperatures. Butter is unstable and breakdown to produce free butyric acid, which gives butter its rancid odour. Old butter and biscuits smell rancid when the butter in them breakdown to yield butyric acid; the more advanced the breakdown, the more rancid the odour.
(ii) Palmitic acid
Palmitic acid has 16 carbon atoms in its backbone and has no carbon double bond (C16:0). It is a saturated fatty acid found in palm oil, which is extracted from the fruits of the oil palm.
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| Wikipedia |
(iii) Stearic acid
Stearic acid is a saturated fatty acid with 18 carbon atoms in its backbone and no carbon double bond (C18:0). It is found in coconut oil.
B. Unsaturated Fatty Acids (UFA)
Unsaturated fatty acids (UFA) contain some double bonds in the carbon backbone. They are grouped into 2 types, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA).
1. Monounsaturated fatty acids (MUFA) contain only one C=C double bond.
2. Polyunsaturated fatty acids (PUFA) contain more than one C=C double bonds.
Examples:
(i) Oleic acid
Oleic acid is a monounsaturated fatty acid (MUFA), and has only one carbon double bond. Olive oil is an unsaturated oil containing oleic acid. Pure olive oil contains oleic acid in addition to other fatty acids. Virgin olive oil contains 99% oleic acid. Keeping virgin olive oil for some time will make it impure.
(ii) Palmitoleic acid
Palmitoleic acid has 16 carbon atoms in its backbone and a single carbon double bond (C16:1). It is a monounsaturated fatty acid (MUFA).
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| Wikipedia |
SATURATED FAT VS, UNSATURATED FAT VS. MIXED FAT
A saturated fat is where the carbon atoms are surrounded by as many hydrogen atoms as possible.
An unsaturated fat has fewer hydrogen atoms than it could have.
A mixed fat has both saturated fatty acids and unsaturated fatty acids.
1-Stearoyl, 2-linoleoyl, 3-palmitoyl glycerol is a mixed triglyceride (mixed fat). It contains 3 fatty acids - stearic acid. linoleic acid, and palmitic acid.
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BENDING IN UNSATURATED FAT MOLECULES: EFFECTS ON PACKING & FORM
A. Tight packing in saturated fats forms solid at RT
If the hydrocarbon chains are saturated with hydrogen, the fatty acid chains are straight and pack themselves close together forming a solid at room temperature (eg animal fat).
Examples:
Most animal fats are saturated and solid at room temperature, eg. butter, tallow, ghee, lard
B. Loose packing in unsaturated fats forms oils at RT
When double bonds form in hydrocarbon chains they cause the long hydrocarbon chains to bend.
In unsaturated fats, presence of one or more double bonds between carbons distort packing; prevent the fatty acid molecules from being able to “stack” or “pack” themselves tightly. Thus, they remain in a liquid state at room temperature (eg vegetable oils).
Examples:
Most plant oils are unsaturated and liquid oils at room temperature, eg sunflower oil, rapeseed oil, corn oil, palm oil
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Monoglyceride
A monoglyceride is formed and water is eliminated when a fatty acid combines with glycerol. The fatty acid joins the glycerol via an ester bond (-C-O-C-). When a monoglyceride is boiled (or acted upon by an esterase enyme), the ester bond is broken, resulting in a glycerol and a free fatty acid.
A monoglyceride combines with a second fatty acid to form a diglyceride, with the elimination of water. The second fatty acid combines at the third carbon position (C3), leaving the second carbon hydroxyl undisturbed. A second ester bond forms at this third carbon. There are 2 ester bonds in a diglyceride, one at C1 and the other at C3.
Triglyceride
A diglyceride combines with a third fatty acid to form a triglyceride, with the release of water. The third fatty acyl chain combines with the hydroxyl at C2. The glycerol moiety now has 3 ester bonds, and forms a polar region. The fatty acyl chains are hydrocarbon chains which are hydrophobic - this region forms the apolar region. Identical or dissimilar fatty acids can combine with glycerol. A mixed triglyceride has different fatty acids. A saturated triglyceride contains all 3 or 2 saturated fatty acids, and is referred to as a saturated fat. An unsaturated triglyceride contains all 3 or 2 unsaturated fatty acids, and is referred to as an unsaturated fat.
Step-wise hydrolysis of triglycerides
Triglycerides are hydrolysed (broken down in aqueous medium and requires water) in a step-wise manner, first to form diglyceride, and then diglyceride to monoglyceride, and finally monoglyceride to glycerol and free fatty acid. Altogether, one triglyceride hydrolyses to one glycerol and 3 free fatty acids.
Hydrolysis of triglycerides by HSL in adipose tissue
In adipose tissue, the enzyme hormone sensitive lipase (HSL) hydrolyses triglycerides before stored fats can be mobilised from adipose tissue.
Fat mobilisation
Fat mobilisation is an important aspect of the regulation of fat metabolism. Fats from adipose tissue are mobilsed during fasting. Plenty of free fatty acids are carried in blood bound to albumin. This gives rise to the presence of high free fatty acid levels in blood. These free fatty acids are brought to the liver.
Fates of fatty acids in the liver
Fatty acids are taken up by liver cells (hepatocytes). The free fatty acids are first activated to from fatty acyl CoA and are then brought into the mitochondrial matrix by the carnitine transport system. Carnitine carries the activated fatty acyl chain into the mitochondrial matrix. Carnitine then dumps the fatty acyl CoA and carnitine is recycled to bring in more fatty acyl CoA.
Burning fatty acids in the liver (by beta-oxidation)
Fatty acids are broken down in a process called beta-oxidation. Please read up and obtain details of beta-oxidation from any clinical biochemistry textbook.
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Endocrine Block 2013/14
In Endocrine Block, I covered 4 topics:
1. Lipid Metabolism (30 April 2014)
2. Regulation of Lipid Metabolism (30 April 2014)
3. Lipoprotein Metabolism (4 May 2014)
4. Cholesterol Metabolism (4 May 2014)
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Practice MCQs
LIPID METABOLISM
1. Regarding lipid metabolism:
A. Activation of fatty acids requires ATP.
B. Carnitine transfers intact free fatty acids.
C. Hormone-sensitive lipase (HSL) degrades triglycerides.
D. Albumin transports plasma free fatty acids.
E. Fatty acid synthesis requires acetyl CoA.
2. Regarding lipid metabolism:
A. Synthesis of palmitic acid involves a multi-enzyme complex.
B. Beta-oxidation of fatty acids produces acetyl CoA.
C. Fat mobilization reduces triglycerides in adipose tissue.
D. Lipolysis involves a lipase.
E. Esterification involves an esterase.
REGULATION OF LIPID METABOLISM
3. Regarding regulation of lipid metabolism:
A. Fasting hydrolyses adipose triglycerides.
B. Starvation causes fat mobilization.
C. Insulin promotes fat storage.
D. Pregnancy reduces body fat.
E. Strenuous exercise depletes body fat.
4. The following reduce body fat:
A. Fasting.
B. Strenuous exercise.
C. Pregnancy.
D. Insulin.
E. Glucagon.
LIPOPROTEIN METABOLISM
5. Regarding lipoprotein metabolism:
A. Chylomicra (CM) transport dietary cholesterol in blood.
B. Very low density lipoproteins (VLDL) are precursors of IDL.
C. Hepatic (B,E)-LDL receptors clear low density lipoproteins (LDL).
D. High density lipoproteins (HDL) remove excess phospholipids.
E. VLDL participate in reverse cholesterol transport.
6. Regarding lipoprotein metabolism:
A. Lipoprotein lipase (LPL) hydrolyses triglyceride-rich lipoproteins.
B. Lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol.
C. Hepatic lipase (HTGL) removes triglycerides from lipoproteins.
D. Acyl cholesterol acyltransferase (ACAT) stores cholesteryl esters.
E. Cholesteryl ester transfer protein (CETP) exchanges lipids between lipoproteins.
CHOLESTEROL METABOLISM
7. Regarding cholesterol metabolism:
A. HMG-CoA reductase is the rate-limiting enzyme in cholesterol synthesis.
B. Cholesterol is synthesized selectively in the liver.
C. All human cells contain cholesterol.
D. Cholesteryl ester is absorbed in the small intestines as free cholesterol.
E. Cholesterol is excreted as bile acids.
8. Regarding cholesterol metabolism:
A. High HDL predisposes to increased heart problems.
B. High LDL cholesterol narrows the arterial lumen.
C. Blood cholesterol levels shift widely during a day.
D. High apoB levels indicate markedly increased LDL in the blood.
E. LDL cholesterol levels are treated in hyperlipidaemia.
Essay
Describe the endogenous lipoprotein pathway with aid of a diagram.
(10 minutes/10 marks)
Proposed Model Answer
Diagram:
(draw a labeled diagram)
Text:
Statements
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Marks
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1.
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Endogenous
pathway happens all the time.
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½
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2.
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It
involves VLDL-LDL metabolism or “LDL cascade” and LDL receptor-mediated
uptake in liver.
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½
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3.
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Synthesis
of VLDL:
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4.
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The
liver synthesizes VLDL. Hepatocytes release nascent VLDL into the Space of
Disse à VLDL
enter sinusoid à VLDL enter systemic circulation.
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½
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5.
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VLDL have
several fates:
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6.
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a)
VLDL transport
triglycerides from liver to peripheral tissues for utilization.
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½
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7.
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b)
When VLDL reach
vascular/capillary beds, they undergo hydrolysis (lipolysis) by LPL where
their triglycerides contents are hydrolysed to free fatty acids (FFAs) and
glycerol.
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½
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8.
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c)
VLDL remnants are
taken up by liver via LDL (B,E) receptors.
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½
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9.
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d)
The VLDL are reduced
in size and are converted into VLDL remnants and IDL, as a result of lipoprotein
lipase (LPL) activity or delipidation.
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½
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10.
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Unesterified
FFAs have several fates:
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11.
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a)
During lipolysis,
some FFA can be carried by plasma albumin and dispersed in plasma for
delivery to other cells. Not much of this happens.
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½
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12.
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b)
Normally, FFA can
enter underlying adipocytes by simple diffusion. Inside the adipocytes, the
FFA are re-esterified to form triglycerides (TG) once more. Adipocytes store
TG until required (as an energy source during fasting or starvation). A
majority of FFA are stored in adipocytes following lipolysis.
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½
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13.
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c)
In times of
starvation, when blood glucose is low and glycogen reserves are low,
triglycerides stored in adipose tissues are hydrolysed by hormone sensitive
lipase (HSL) and the FFAs are released from adipose tissue. FFAs then attach
to circulating albumin and are brought to liver for beta-oxidation, for continued energy supply.
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½
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14.
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IDL have
several fates:
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15.
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a)
IDL can be converted
into LDL by LPL in blood (intravascular).
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½
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16.
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b)
IDL can be taken up
by hepatic receptors.
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½
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17.
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c)
IDL can be converted
into LDL by hepatic lipase (HTGL) in liver.
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½
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18.
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LDL have
several fates:
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19.
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a)
Normally, LDL are taken up by hepatic LDL (B,E) receptors. The
contents of LDL are broken down into FC, CE, PL, TG/ DG/ MG/ FFA and amino
acids. These are kept within the hepatocytes or recycled for use by other
cells. Hepatic contents of FC and CE are regulated by acyl cholesterol
acyltransferase (ACAT). Few things can happen if cholesterol is low,
specifically in the cell or in the blood. If there is low cellular FC, stored
cholesterol (as cholesteryl ester, CE) is broken down to free cholesterol
(FC) by ACAT. If there is low plasma FC, the liver cell makes more FC via increased
HMG-CoA reductase activity. The 2 enzymes, ACAT and HMG-CoA reductase, are
sensitive to cellular and blood cholesterol levels, and combined, they
regulate cholesterol levels in cells and blood.
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½
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20.
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b)
LDL can also deliver
its contents directly to cells, eg adrenal glands, for
synthesis of steroid hormones.
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½
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21.
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c)
Under abnormal levels of LDL in the blood (eg hyperlipidaemia),
LDL can be taken up by the scavenger receptors present on extrahepatic
tissues (EHT).
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½
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22.
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d)
LDL apoB-100 will be
oxidized due to the prolonged presence of LDL in the blood. Also, the LDL
particle is now smaller and apoB-100 is not stable at this stage. ApoB-100
becomes easily oxidised. Oxidised apoB-100 has higher affinity for
macrophages. Thus, oxidised LDL will be taken up by macrophages in EHT.
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½
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23.
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e)
Macrophages contain
scavenger receptors on their surface. Macrophages are present on blood vessel
walls. Oxidised LDL will attach to the receptors and be internalised.
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½
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24.
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f)
The oxidised LDL are
hydrolysed into component cholesterol, fatty acids, glycerol and amino acids,
which are stored within the macrophages.
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½
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25.
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g)
This uptake of
oxidised LDL is unregulated (ie, not controlled). The macrophages take up as
much LDL until they stop functioning and die off, becoming foam cells.
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½
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