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Dr.

LOO HIAN DAO

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INTRODUCTION of LIPIDS
 common property of lipid:
 relatively insoluble in water and
 soluble in nonpolar solvents such as ether and chloroform.
 high energy value

 fat-soluble vitamins (A,D,E,K)
 thermal insulator in the subcutaneous tissues and around certain
organs.
 electrical insulators, allowing rapid propagation of depolarization
waves along myelinated nerves.
 transporting lipids (lipid + protein  lipoprotein

CLASSIFIED
 Simple lipids: Esters of fatty acids with various alcohols.
 a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state.
 b. Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols.

 Complex lipids: Esters of fatty acids containing groups in addition to an

alcohol and a fatty acid.
 a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a

phosphoric acid residue. They frequently have nitrogen containing bases and other
substituents, eg, in glycerophospholipids the alcohol is glycerol and in
sphingophospholipids the alcohol is sphingosine.
 b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and
carbohydrate.
 c. Other complex lipids: Lipids such as sulfolipids and aminolipids. Lipoproteins
may also be placed in this category.

 Precursor and derived lipids: These include fatty acids, glycerol,

steroids, other alcohols, fatty aldehydes, ketone bodies, hydrocarbons, lipidsoluble vitamins, and hormones.

gestion and absorption of triacylglycerols .

LIPOGENESIS .

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Elongation of Fatty A cid C hains  This pathway (the “microsomal system”) elongates saturated and unsaturated fatty acylCoAs (from C10 upward) by two carbons. using malonyl-CoA as acetyl donor and NADPH as reductant. and is catalyzed by the microsomal fatty acid elongase system of enzymes .

as in diabetes mellitus. or when there is a deficiency of insulin. .  These latter conditions are associated with increased concentrations of plasma free fatty acids.R EG U LATES LIP O G EN ESIS  Lipogenesis converts surplus glucose and intermediates such as pyruvate. assisting the anabolic phase of this feeding cycle.  Lipogenesis is depressed under conditions of restricted caloric intake. and acetyl-CoA to fat.  Lipogenesis is increased when succrose is fed instead of glucose because fructose bypasses the phosphofructokinase control point in glycolysis and floods the lipogenic pathway. on a fat diet. and an inverse relationship has been demonstrated between hepatic lipogenesis and the concentration of serum-free fatty acids. lactate.

 Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol.  Acyl-CoA causes an inhibition of pyruvate dehydrogenase by inhibiting the ATP-ADP exchange transporter of the inner mitochondrial membrane.  Acyl-CoA may also inhibit the mitochondrial tricarboxylate transporter. which leads to increased intramitochondrial [ATP]/[ADP] ratios and therefore to conversion of active to inactive pyruvate dehydrogenase. .R egulation of Lipogenesis  Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate. and long-chain acyl-CoA inhibits its activity. which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA.

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 Peroxisomes Oxidize Very Long Chain Fatty Acids and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step). which is broken down by catalase.  Hence.  These enzymes are induced by high-fat diets and in some species by hypolipidemic drugs such as clofibrate. a constituent of the citric acid cycle. the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic.  This compound is converted to succinyl-CoA. Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation. producing acetyl-CoA. until a three-carbon (propionyl-CoA) residue remains. .

KETOGENESIS .

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the liver .Im paired O xidation of Fatty A cids G ives R ise to D iseases O ften A ssociated w ith H ypoglycem ia  C arn itin e d ef i cien cy  in the new born— and especially in preterm infants  Hypoglycemia. impaired fatty acid oxidation and lipid accumulation  muscular weakness  Treatment is by oral supplementation with carnitine  CPT-I deficiency: only the liver  CPT-II deficiency affects primarily skeletal muscle and. when severe.

.  inactivates medium.and short-chain acyl-CoA dehydrogenase. inhibiting -oxidation and causing hypoglycemia. which contains the toxin hypoglycin.Im paired O xidation of Fatty A cids G ives R ise to D iseases O ften A ssociated w ith H ypoglycem ia  Jam aican vom itin g sickn ess  caused by eating the unripe fruit of the akee tree .

causing ketoacidosis. This may be fatal in uncontrolled diabetes mellitus.  However.KETOACIDOSIS  Higher than normal quantities of ketone bodies present in the blood or urine constitute ketonemia (hyperketonemia) or ketonuria. respectively. The overall condition is called ketosis. . their continual excretion in quantity progressively depletes the alkali reserve.  Acetoacetic and 3-hydroxybutyric acids are both moderately strong acids and are buffered when present in blood or other tissues.

Arachidonic acid can be formed from linoleic acid. but never beyond the Δ9 position. Δ6. and Δ9 positions in most animals. .METABOLISM OF UNSATURATED FATTY ACID Linoleic and -linolenic acids are known as the nutritionally essential fatty acids. plants are able to synthesize the nutritionally essential fatty acids by introducing double bonds at the Δ12 and Δ15 positions. Δ5. In contrast. Double bonds can be introduced introduced at the Δ4.

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METABOLISM OF UNSATURATED FATTY ACID Several tissues including the liver are considered to be responsible for the formation of nonessential monounsaturated fatty acids from saturated fatty acids. MONOUNSATURATED FATTY ACIDS ARE SYNTHESIZED BY Δ 9 DESATURASE SYSTEM in the endo plasmic reticulum will catalyze the conversion of palmitoyl-CoA or stearoylCoA to palmitoleoyl-CoA or oleoyl-CoA SYNTHESIS OF POLYUNSATU RATED FATTY ACIDS INVOLVES DESATURASE & ELONGASE ENZYME SYSTEMS .

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. such as asthma. and E4. D4. Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4. Their synthesis is specifically inhibited by low-dose aspirin. This mixture of leukotrienes is a potent constrictor of the bronchial airway musculature. Prostacyclins (PGI2) are produced by blood vessel walls and are potent inhibitors of platelet aggregation. These leukotrienes together with leukotriene B4 also cause vascular permeability and attraction and activation of leukocytes and are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions.EICOSANOIDS  Thromboxanes are synthesized in platelets and upon release cause     vasoconstriction and platelet aggregation.

ESTERIFICATION .

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TYPE of PHOSPHOLIPID + SPHYNGOLIPID Gliserolipid Triasilgliser ol Simpanan adiposa Lipoprotein darah Gliserofosfolipi d Fosfatidilkolin (lesitin) Fosfatidiletanolamin (sefalin) Fosfatidilserin Fosfatidil inositol bisfosfat Fosfatidilgliserol Kardiolipin Fosfolipid Eter gliserolipid Plasmalogen PAF Sphingolipid Sphingofosfoli pid Sfingomielin Glikolipid Serebrosida Sulfatida Globosida Gangliosida .

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eg.  Inositol phospholipids in the cell membrane act as precursors of hormone second messengers. . which is lacking in respiratory distress syndrome of the newborn. and platelet-activating factor is an alkylphospholipid.Phospholipids  Some phospholipids have specialized functions. dipalmitoyl lecithin is a major component of lung surfactant.

containing sphingosine and sugar residues as well as fatty acid and found in the outer leaflet of the plasma membrane with their oligosaccharide chains facing outward. .G lycosphingolipids  Glycosphingolipids. the toxin that causes cholera). and  (3) as ABO blood group substances.  (2) as receptors for bacterial toxins (eg. form part of the glycocalyx of the cell surface and are important  (1) in cell adhesion and cell recognition.

LIPID TRANSPORT
 Four major groups of lipoproteins have been

identified that are important physiologically
and in clinical diagnosis. These are
 (1) chylomicrons, derived from intestinal

absorption of triacylglycerol and other lipids;
 (2) very low density lipoproteins (VLDL, or
pre-β-lipoproteins), derived from the liver for
the export of triacylglycerol;
 (3) low-density lipoproteins (LDL, or βlipoproteins), representing a final stage in the
catabolism of VLDL; and
 (4) high-density lipoproteins (HDL, or αlipoproteins), involved in VLDL and chylomicron
metabolism and also in cholesterol transport.

LIPID TRANSPORT

Apolipoproteins
 Apolipoproteins carry out several roles:
 (1) they can form part of the structure of the

lipoprotein, eg, apo B;
 (2) they are enzyme cofactors, eg, C-II for
lipoprotein lipase, A-I for lecithin:cholesterol
acyltransferase, or enzyme inhibitors, eg, apo
A-II and apo C-III for lipoprotein lipase, apo C-I
for cholesteryl ester transfer protein;
 and (3) they act as ligands for interaction with
lipoprotein

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Lower risk Higher risk 130 mg/dL Large LDL (Pattern A) 130 mg/dL LDL Cholesterol Balance Small LDL (Pattern B) But they also have more particles! .20+ years of studies: Patients with smaller LDL size have greater CHD risk at any given level of LDL-C.

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in starvation).  This occurs during starvation and the feeding of high-fat diets. .  The first type is associated with raised levels of plasma free fatty acids resulting from mobilization of fat from adipose tissue or from the hydrolysis of lipoprotein triacylglycerol by lipoprotein lipase in extrahepatic tissues. fatty infiltration is sufficiently severe to cause visible pallor (fatty appearance) and enlargement of the liver with possible liver dysfunction.  The ability to secrete VLDL may also be impaired (eg. In uncontrolled diabetes mellitus.  The production of VLDL does not keep pace with the increasing influx and esterification of free fatty acids. and ketosis in cattle. twin lamb disease. causing a fatty liver. allowing triacylglycerol to accumulate.FATTY LIVER  Fatty livers fall into two main categories.

the lesion may be due to  (1) a block in apolipoprotein synthesis. .  Theoretically.  (2) a block in the synthesis of the lipoprotein from lipid and apolipoprotein.  (3) a failure in provision of phospholipids that are found in lipoproteins. or  (4) a failure in the secretory mechanism itself. thus allowing triacylglycerol to accumulate.FATTY LIVER  The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins.

inflammatory and fibrotic changes may develop leading to nonalcoholic steatohepatitis (NASH). hepatocarcinoma. which can progress to liver diseases including cirrhosis. and liver failure.Nonalcoholic fatty liver disease  Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. .  When accumulation of lipid in the liver becomes chronic.

alcoholic fatty liver disease  Alcoholic fatty liver is the first stage in alcoholic liver disease (ALD) which is caused by alcoholism and ultimately leads to cirrhosis.  Changes in the [NADH]/[NAD+ ]  Oxidation of ethanol by alcohol dehydrogenase leads to excess production of NADH. .

aggravating gout. . resulting in hyperlacticacidemia. which decreases excretion of uric acid.The increased [NADH]/[NAD+ ] ratio also causes increased [lactate]/[pyruvate].

eg. by competing for cytochrome P450-dependent enzymes. . barbiturates.  Ethanol also inhibits the metabolism of some drugs.  This system increases in activity in chronic alcoholism. Some metabolism of ethanol takes place via a cytochrome P450-dependent microsomal ethanol oxidizing system (MEOS) involving NADPH and O2 .

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Impairment of Other Metabolic Processes MALATE-ASPARTATE SHUTTLE ↑ NADH/NAD+↑ GLYCEROL 3-P ↑ RESPIRATORY CHAIN INHIBITED of GLUCONEOGENESIS LACTATE/PYRUVATE ↑ INHIBITED of TCA CYCLE ACETYL-CoA ↑ HYPOGLYCEMIA LIPOGENESIS ↑ LACTIC ACIDOCIS FFA ↑ EXCRETION of URIC ACID ↓ TRIACYLGLYCEROL ↑ HYPERLIPIDEMIA HYPERURICEMIA KETOGENESIS ↑ KETOSIS CHOLESTERO GENESIS FATTY LIVER HYPERCHOLESTEROL .

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Adipose tissue secretes hormones such as adiponectin. and leptin. . which modulates glucose and lipid metabolism in muscle and liver. which regulates energy homeostasis.

Thermogenesis results from the presence of an uncoupling protein.BROWN ADIPOSE TISSUE Brown adipose tissue is the site of “nonshivering thermogenesis. thermogenin. in the inner mitochondrial membrane. .” It is found in hibernating and newborn animals and is present in small quantity in humans.

 Cholesterol is an amphipathic lipid and as such is an essential structural component of membranes and of the outer layer of plasma lipoproteins. and brain.  As a typical product of animal metabolism. liver. bile acids.Cholesterol  Cholesterol is present in tissues and in plasma either as free cholesterol or as a storage form. cholesterol occurs in foods of animal origin such as egg yolk.  It is synthesized in many tissues from acetyl-CoA and is the precursor of all other steroids in the body such as corticosteroids. meat. combined with a long-chain fatty acid as cholesteryl ester. and vitamin D. sex hormones. .

Stage 1 Acetyl CoA (C2) HMG-CoA NADPH HMG-CoA Reductase NADP+ Mevalonate (C6) Stage 2 Mevalonate 3ATP 3ADP CO2 Active Isoprenoids (C5) Several NADPH Condensation Steps NADP+ Squalene (C30) Biosynthesis of cholesterol rate-determining step cholesterol is feedback inhibitor mevalonate is feedback inhibitor target site for statin drugs Stage 3 Squalene (C30) Cyclization O2 NADPH Squalene epoxidase/ + NADP cyclase Lanosterol (C30) (4-ring structure) Stage 4 Lanosterol (C30) O2 NADPH (19 steps) 3 CH3 NADP+ Cholesterol (C27) The ER is the primary site of cholesterol synthesis .

.HMG-CoA reductase. the key rate-limiting enzyme in the cholesterol biosynthetic pathway.

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XANTHELASMA .

. causing increased bile acid synthesis in the liver.TH ERAPY ofH YPERCH O LESTERO LEM IA  Significant reductions of plasma cholesterol can be effected medically by the use of cholestyramine resin or surgically by the ileal exclusion operations. lowering plasma cholesterol.  This increases cholesterol excretion and up-regulates LDL receptors.  Sitosterol is a hypocholesterolemic agent that acts by blocking the absorption of cholesterol from the gastrointestinal tract.  Both procedures block the reabsorption of bile acids.

and pravastatin.TH ERAPY ofH YPERCH O LESTERO LEM IA  The formation of cholesterol at various stages in the biosynthetic pathway.  Statins currently in use include atorvastatin.  The statins inhibit HMGCoA reductase. simvastatin. thus upregulating LDL receptors. .

 Probucol appears to increase LDL catabolism via receptorindependent pathways. they stimulate hydrolysis of VLDL triacylglycerols by lipoprotein lipase.  In addition. . in arterial walls. but its antioxidant properties may be more important in preventing accumulation of oxidized LDL.  Nicotinic acid reduces the flux of FFA by inhibiting adipose tissue lipolysis.TH ERAPY ofH YPERCH O LESTERO LEM IA  Fibrates such as clofibrate and gemfibrozil act mainly to lower plasma triacylglycerols by decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver. which has enhanced atherogenic properties. thereby inhibiting VLDL production by the liver.

Lipoprotein (a)  Type of LDL bound to ApoB and Apo(a)  Prothrombotic  Binding domain similar to plasminogen. may compete. favoring thrombosis  Proatherogenic  preferentially binds oxidized phospholipids and taken up into atheromatous plaques .

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Lipoprotein (a) .