9. lipids and lipoproteins
TRANSCRIPT
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LIPID CHEMISTRY
AND
METABOLISM
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Contents
1. Lipid Chemistry
2. Lipid Classes
3. Lipid Synthesis4. Metabolism
5. Lipid Disorders
6. Lipid and Lipoprotein Analyses
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Lipid Chemistry
Introduction
Composed of mostly carbons-hydrogen (C-H) bonds
Classification of Medically Important lipids:
1. Fatty acids2. Triglycerides
3. Cholesterol
4. Phospholipids
Transported by lipoproteins (VLDL, LDL, HDL)
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Classes of lipids in General
Classes of Lipids
By Function By Structures
torage Messenger Simple Sterol Derived
Membrane Compound Miscellaneous
Fats/Oil Waxes
Phospholipids Glycolipids
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Lipid Chemistry
1. Fatty Acids
1. Fatty Acids
• Linear chains of C-H bonds that terminated with -COOH
1. Fatty Acids
• Linear chains of C-H bonds that terminated with -COOH
• Classifications:
a. unesterified bound to albumin
b. esterified constituent of triglycerides/phospholipids
1. Fatty Acids
• Linear chains of C-H bonds that terminated with -COOH
• Classifications:
a. unesterified bound to albumin
b. esterified constituent of triglycerides/phospholipids
g. saturated no double bonds
h. monosaturated
one double bondi. polyunsaturated ≥double bonds
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Lipid Chemistry
1. Fatty Acids
Linear chains of C-H bonds that terminated with -COOH
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Lipid Chemistry
2. Triglyceride
a. Contain 3 FA attached to one molecule of glycerol
2. Triglyceride
a. Contain 3 FA attached to one molecule of glycerol
b. Contain saturated fatty acids or unsaturated fatty acids
2. Triglyceride
a. Contain 3 FA attached to one molecule of glycerol
b. Contain saturated FA’s or unsaturated f=FA’s
c. No charged groups, water insoluble, neutral lipid
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Lipid Chemistry
3. Phospholipids3. Phospholipids
a. Contain 2 FA’s attached to one molecule of glycerol
3. Phospholipids
a. Contain 2 FA’s attached to one molecule of glycerol
b. Third position contain phospholipid head groups
3. Phospholipids
a. Contain 2 FA’s attached to one molecule of glycerol
b. Third position contain phospholipid head groups
c. Amphipathic
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Lipid Chemistry
3. Phospholipids
a. Contain 2 FA’s
attached to one
molecule ofglycerol
b. Third position
contain
phospholipidhead groups
c. Amphipathic
Lecithin
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Lipid Chemistry
4. Cholesterol4. Cholesterol
a. Unsaturated steroid alcohol contain four rings
4. Cholesterol
a. Unsaturated steroid alcohol contain four rings
b. Amphipathic
4. Cholesterol
a. Unsaturated steroid alcohol contain four rings
b. Amphipathic
c. Classifications:
4. Cholesterol
a. Unsaturated steroid alcohol contain four rings
b. Amphipathic
c. Classifications:
i. unesterified free cholesterol (amphipathic)
ii. esterified cholesteryl ester (neutral lipid)
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Lipid Chemistry
4. Cholesterol4. Cholesterol
Converted to:
4. Cholesterol
Converted to:
a. Bile salts
4. Cholesterol
Converted to:
a. Bile salts
b. Steroid hormones
4. Cholesterol
Converted to:
a. Bile salts
b. Steroid hormones
c. Vitamin D and Cell membrane
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Lipid Chemistry
Chemical Structure of Lipids
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Lipoprotein Structure
COMPONENTS
Lipids and proteins
COMPONENTS
Lipids and proteins
Composition:
COMPONENTS
Lipids and proteins
Composition:
a. Free cholesterol and
phospholipids are on
the surface
COMPONENTS
Composition:
a. Free cholesterol and
phospholipids are on
the surface
b. Triglycerides and
cholesteryl esters are
in the core regions
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Lipoprotein Structure
Apolipoprotein
Apo A-I
Apo A-II
Apo A-IV
Apo B-100
Apo B-48
Apo C-I
Apo C-II
Apo C-III
Apo E
Apo(a)
Characteristics of the Major Human ApolipoproteinsApolipoprotein Major LPP Location
Apo A-I HDL
Apo A-II HDL
Apo A-IV Chylos, VLDL, HDL
Apo B-100 LDL, VLDL
Apo B-48 Chylos
Apo C-I Chylos, VLDL, HDL
Apo C-II Chylos, VLDL, HDL
Apo C-III Chylos, VLDL, HDL
Apo E VLDL, HDL
Apo(a) Lp(a)
Apolipoprotein Major LPP Location Function
Apo A-I HDL LCAT activator, ABCA1 lipid acceptor
Apo A-II HDL inactivates LCAT
Apo A-IV Chylos, VLDL, HDL
Apo B-100 LDL, VLDL LDL receptor ligand
Apo B-48 Chylos Remnant receptor ligand
Apo C-I Chylos, VLDL, HDL
Apo C-II Chylos, VLDL, HDL LPL cofactor
Apo C-III Chylos, VLDL, HDL LPL inhibitor
Apo E VLDL, HDL LDL receptor Ligand
Apo(a) Lp(a) plasminogen inhibitor
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Lipoprotein Structure
MAJOR TYPES
1. Chylomicrons
2. VLDL
3. LDL
4. HDL
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Lipoprotein Structure
Characteristics of the Major Human Lipoproteins
Characteristics
Density (g/mL)
Diameter (nm)
Total lipid (%)
Triglyceride (%)
Cholesterol (%)
Major Protein
Characteristics Chylo.
Density (g/mL) <0.93
Diameter (nm) 80-1,200
Total lipid (%) 98
Triglyceride (%) 84
Cholesterol (%) 7
Major Protein Apo B-48
Characteristics Chylo. VLDL
Density (g/mL) <0.93 0.93-1.006
Diameter (nm) 80-1,200 30-80
Total lipid (%) 98 89-96
Triglyceride (%) 84 44-60
Cholesterol (%) 7 16-22
Major Protein Apo B-48 Apo B-100
Characteristics Chylo. VLDL LDL
Density (g/mL) <0.93 0.93-1.006 1.019-1.063
Diameter (nm) 80-1,200 30-80 18-30
Total lipid (%) 98 89-96 77
Triglyceride (%) 84 44-60 11
Cholesterol (%) 7 16-22 62
Major Protein Apo B-48 Apo B-100 Apo B-100
Characteristics Chylo. VLDL LDL HDL
Density (g/mL) <0.93 0.93-1.006 1.019-1.063 1.063-1.21
Diameter (nm) 80-1,200 30-80 18-30 5-12
Total lipid (%) 98 89-96 77 50
Triglyceride (%) 84 44-60 11 3
Cholesterol (%) 7 16-22 62 19
Major Protein Apo B-48 Apo B-100 Apo B-100 Apo A-1
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Lipoprotein Structure
MAJOR TYPES
1. Chylomicrons
• Largest and least dense
• Produced in the intestine
• Delivery of dietary lipids to hepatic and peripheral cells
Tube of turbid plasma
left overnight in a
refrigerator at 4OC
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Lipoprotein Structure
MAJOR TYPES
2. Very Low Density Lipoproteins
• Pre-β- lipoprotein
• Produced in the Liver
• Transfer triglycerides from the liver to peripheral tissue
Tube of turbidplasma left
overnight in a
refrigerator at
4OC
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Lipoprotein Structure
MAJOR TYPES
3. Low Density Lipoproteins (LDL)
• β-lipoprotein or bad cholesterol
• Formed from lypolysis of VLDL to IDL then to LDL
• Transfer dietery cholesterol to peripheral tissues
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Lipoprotein Structure
MAJOR TYPES
4. High Density Lipoproteins (HDL)
• α-LPP or good cholesterol
• Produced in the Liver and the Intestine
• Transfer cholesterol from peripheral cells back to the liver
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Lipoprotein Structure
MINOR TYPES
5. Lipoprotein(a)
• LDL lipoprotein like particle
• ↑ Confers increased risk for premature coronary heartdisease and stroke.
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Lipoprotein Structure
MAJOR TYPES
1. Chylomicrons
2. VLDL
3. LDL
4. HDL
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Analyte Reference RangeConversion
Factor (mmol/L)
Total cholesterol 140-200 mg/dL 0.026
HDL cholesterol 40-75 mg/dL
LDL cholesterol 50-130 mg/dL
Triglyceride 60-150 mg/dL 0.011
Adult reference ranges for Lipids
Lipoprotein Structure
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Liver Adipose tissues Skeletal muscle
Dietary lipid
Digestion (bile)
Fatty acid + monoglyceride
Absorption
Triglyceride
Chylomicrons
Transport
Overview of Lipid Metabolism
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Ketone bodies Formation
Ketone bodies, also known as ketones,are water-soluble compounds that areproduced as by-products of fatty acidsoxidation.The
The three endogenous ketone bodiesare
Acetoacetic acid
Acetone,
Beta-hydroxybutyric acid.
Production of these compounds is calledketogenesis.
Ketone bodies are synthesized from theAcetyl CoA molecules produced
from the β-oxidation of fatty acid Glycolysis. Instead of entering the
citric acid cycle, some acetyl-CoA isconverted to ketone bodies in the livermitochondria.
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Ketone bodies Formation
Step 3: Ketone bodies aretransported to other tissuessuch as brain, muscle and heartwhere they are converted backto acetyl-CoA to serve as sourceof energy.
Normally, the brain uses only glucose for energy, butduring starvation and high-fat/low carbohydrate diet,the glucose level becomes low. In this condition,ketone bodies can become the main energy source forthe brain.
When excess ketone bodies accumulate in the blood,the condition is called ketonemia.
This condition decreases the blood pH to acidic levels
which could lead to a state called ketoacidosis. T The accumulation of the ketone bodies in the blood
which lead to ketonemia and ketoacidosis is generallyreferred to ketosis.
This condition happens most often in untreated Type Idiabetes mellitus. A diabetic person has
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Metabolic Fate of Ketone Bodies
Ketone bodies are transported from the liver to other
tissues such as brain, muscle and heart.
The acetoacetate and beta-hydroxybutyrate can be
reconverted to acetyl-CoA to produce energy via thecitric acid cycle.
Acetone cannot be converted back to acetyl-CoA, so it
is excreted in the urine or exhaled because of its
characteristic high vapor pressure.
Therefore, acetone is responsible for the characteristic
"fruity" odor of the breath of persons in ketoacidosis.
Comparison of Fatty Acid Catabolism and
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Fatty Acid Catabolism Fatty Acid Anabolism
Occurs in mitochondrial matrix Occurs in the cytoplasm
Acetyl CoA – product Acetyl CoA - precursor
Malonyl CoA – not involved Malonyl CoA – source of 2 carbon
Biotin not required Biotin required
Oxidative process Reductive process
Requires NAD and FAD Requires NADPH
Produce ATP Require ATP
Form thioesters with CoA-SH Form thioesters with acyl carrier proteins (ACP-SH)
No ordered aggregate of enzymes With ordered multienzyme complex
β-hydroxyacyl intermediates have L-
configuration
β-hydroxyacyl intermediates have D-configuration
Comparison of Fatty Acid Catabolism and
Anabolism
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Fatty Acid Anabolism
Fatty acids are synthesized from acetyl CoA.
The major source of acetyl CoA is the carbohydrates.
Therefore excess intake of carbohydrate can be converted to fats.
Acetyl CoA is needed in the synthesis of fatty acid and fatty acid is needed in thesynthesis of triglyceride which is the storage form of lipids in the body.
This complex process of biosynthesis of fats is referred to as lipogenesis.
The reductive synthesis of fatty acids is a cytoplasmic process carried out by amultienzyme complex called the acyl carrier protein (ACP).
The reduction-oxidation steps require nicotinamide adenine dinucleotide
phosphate (NADPH). There are series of steps: ACP Formation, Condensation, Hydrogemation,
Dehydration, and hydrogenation.
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Steps in fatty acid biosynthesis
Acp Complex Formation
Step 1: Transfer of acetylgroup to acyl carrierprotein (ACP) with noenergy input. Thereaction is catalyzed byacetyltransferase andmalonyl CoA. .
Step 2: Malonyl CoA isadded to the ACP which iscatalyzed bymalonyltransferase and
malonyl –ACP is formed..
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Steps in fatty acid Biosynthesis
Elongation Chain
Step 3: Acetyl group is transferred to the malonyl
group with the release of carbon dioxide which is
catalyzed by β-ketoacyl-synthase and Acetoacetyl-ACP is formed.
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Steps in fatty acid Biosynthesis
Step 4: Keto group is reduced to a hydroxyl group
by the beta-ketoacyl reductase activity to form
Beta-hydroxybutyryl-ACP
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Steps in fatty acid Biosynthesis
Step 5: Beta-hydroxybutyryl-ACP is dehydrated toform a trans- monounsaturated fatty acyl groupcatalyzed by β-hydroxyacyl dehydratase in the formof crotonyl-ACP and oxidized NADP and water.
Step 6: Double bond is reduced by NADPH, yielding
a saturated fatty acyl group (Butyryl –ACP) twocarbons longer than the initial one. It is catalyzedby enoyl-reductase.
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Regulation of Fatty Acid Metabolism.
Fatty acid metabolism is regulated by theaction of hormone, feedback inhibitionand feed-forward activation.
The free fatty acids from the adiposetissue are used as energy when insulinlevel is low. Insulin controls the storageand release of fatty acids in and out ofthe adipose tissue.
When there is low insulin level and highglucagon level, the fatty acids will bereleased from the adipose tissue.
Then it will be converted into ketonebodies in the liver.
Therefore, fatty acid oxidation and
ketone body synthesis is activated byglucagon.
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Metabolic Fate of Fatty Acid
Fatty acids are stored in the form of triglyceride primarily inadipose tissue.
Triglycerides must be hydrolyzed to release the fatty acids whichare oxidized to acetyl CoA for energy.
Fatty acids can also be converted to ketone bodies which can beused as source of energy for extrahepatic tissues.
They also attach to a phosphate group to form thephospholipidsthat composed the cell membranes.Fatty acids are
used for the biosynthesis of bioactive molecules such asarachidonic acid and eicosanoids.Cholesterol, steroids and steroidhormones are all derived from fatty acids.
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ANABOLISM OF CHOLESTEROL
Cholesterol is widely distributed in the body because of its variousroles. It is a biosynthetic precursor of bile acids, vitamin D andsteroid hormones.
Cholesterol is abundant in the tissue of the brain and nervoussystem where it contributes to the functioning of ‘synapses' which
allow nerves to communicate with each other.
Exogenous cholesterol is derived in the diet while endogenous arethose synthesized by the body.
Cholesterol is produced in the liver and stored in the gallbladder.Cholesterol biosynthesis involved five major steps:
o es ero osyn es s nvo ve ve
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o es ero osyn es s nvo ve vemajor steps:
1. Acetoacetyl-CoA is converted to 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) which is catalyzed
by HMG-CoA synthase.
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Steps in biosynthesis of Cholesterol
2. HMG-CoA is converted to mevalonate which is catalyzed by HMG-CoA
reductase
3. Mevalonate is converted to isopentenyl pyrophosphate (IPP) with the
release of CO2
.
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4. IPP is converted to squalene.
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5. Squalene is converted to cholesterol.
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Fate of Cholesterol
Cholesterol can be stored in thegall bladder or transported tothe cell membranes where it canbe used to synthesize or repairthe membranes.
Stored cholesterol in the
gallbladder can be concentratedand lead to the formation of gallstones.
Since the body synthesizesenough cholesterol, excessendogenous cholesterol may
builds up in the walls of arteriesand form hard structures calledplaques.
The hardening of the arteries isknown as atherosclerosis
Cholesterol can be recycled backto the liver, therefore only asmall amount is excreted.
The cholesterol that is excretedis first converted to the watersoluble bile acids or bile salts.
Cholesterol that is not excretedcan be used in the synthesis ofvarious classes of steroidhormones.
There are five groups of steroid hormones synthesized from
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cholesterol which perform various metabolic functions:
Steroid hormones Metabolic Function
Glucocorticoid Stimulation of gluconeogenesis
Enhance the expression of enzymes involved in gluconeogenesis
Mobilization of amino acids from extrahepatic tissues
Inhibition of glucose uptake in muscle and adipose tissue
Stimulation of fat breakdown in adipose tissue
Mineralocorticoids Aldosterone acts on the kidneys to provide active reabsorption of
sodium and an associated passive reabsorption of water, as well as
the active secretion of potassium
Androgens Inhibit the ability of some fat cells to store lipids by blocking a
signal transduction pathway that normally supports adipocyte
function
Estrogen Increase hepatic production of binding proteins
Progestogens Precursors to other steroids
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Steroidogenesis is the process of steroid hormone production in living organisms. This
process requires several oxidative enzymes located in both mitochondria and endoplasmic
reticulum.The biosynthetic pathway for different steroid hormones is depicted in Figure
13.7
na o sm o omp ex an er ve
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na o sm o omp ex an er velipid
Complex lipids include the glycerolipids, for which
glycerol is the backbone, and sphingolipids, which
are built on a sphingosine backbone.
The phospholipids, which include both
glycerophospholipids and sphingomyelins, are
crucial components of membrane structure.
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The biosynthetic precursor of glycerolipids is phosphatidic acid. Phosphatidic acid
is derived from the phosphorylation of glycerol to form glycerol-3-phosphate
which is catalyzed by glycerokinase.
It is also synthesized from dihydroxyacetone phosphate (DHAP) which
can be reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase.
Another way is the addition of first acyl chain to the DHAP catalyzed by
acyltransferase.
It is followed by reduction of the backbone keto group by
acyldihydroxyacetone phosphate reductase, using NADPH as the reductant. Then
the phosphatidic acid is converted directly to glycerolipids which is catalyzed by
phosphatidate cytidyltransferase.
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Sphingolipid Biosynthesis
Sphingolipids are present in myelinsheath that insulates nerve axons.
The initial reaction, which involvescondensation of serine and palmitoyl-CoA with release of bicarbonate, iscatalyzed by 3-ketosphinganine
synthase. Reduction of the ketone product to form
sphinganine is catalyzed by 3-keto-sphinganine reductase, with NADPH as areactant.
Then sphinganine is acylated to form N-
acyl sphinganine, which is thendesaturated to form ceramide.Ceramide is the building block for allother sphingolipids. (Figure 13.16)
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Eicosanoid Biosynthesis
Eicosanoids arecyclopentanoic acids derivedfrom the fatty acid which isthe arachidonic acid.
They include prostaglandins,
thromboxanes,prostacyclins,andleukotrienes.
Eicosanoids are not storedwithin cells, but aresynthesized whenever the
body needs them. Usually theyare release in the
body during inflammation.
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Prostaglandinisoriginally shown to be synthesized
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g g y y
in the prostate gland. One of the important function of
prostaglandin is the contraction and relaxation of smooth
muscle tissue.Prostaglandins are autocrine or paracrine
hormones which exert effect on the immediate vicinity of
the site of their secretion.
Prostacyclin is produced in endothelial cells from prostaglandinby the action of the
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y p p g y
enzyme prostacyclin synthase. (Figure 13.17) Prostacyclin inhibits platelet
activation thus preventing the formation of the platelet plug which is involved in
blood clot formation.
Thromboxaneisproduced by activated platelets from prostaglandin by the
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Thromboxaneisproduced by activated platelets from prostaglandin by the
action of the enzyme thromboxane synthase. It act as vasoconstrictorand it
facilitate platelet aggregation. (Figure 13.17)
Leukotriene was first found in leukocytes It is produced in the
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Leukotriene was first found in leukocytes. It is produced in the
body from arachidonic acid by the activity of the enzyme 5-
lipoxygenase.(Figure 13.17) It triggers contractions in the smooth
muscles lining the trachea and their overproduction is a majorcause of inflammation in asthma and allergic rhinitis.
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