Metabolism of lipids

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Metabolism of lipids
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Course Content

• Digestion and absorption of lipids
• Triacylglycerol metabolism
• Phospholipid metabolism
• Cholesterol metabolism
• plasma lipoprotein metabolism

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Summary

• Definition
• Classes

fats triacylglycerols, TG
cholesterol, Ch
lipids
cholesteryl ester, CE
lipoids
phospholipids, PL
glucolipids, GL

• Function

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nomenclature

• Fatty acids
• Saturated fatty acids
• 14?20C palmitic acid
• 16C stearic acid 18C
  
• Unsaturated fatty acids
• Linolenic acid 18C three unsaturated
  bonds
• Linoleate 18C two unsaturated bonds
• Arachidonic acid 20C
  four unsaturated bonds
• Essential fatty acids
• required for the growth of mammals and they
  must be obtained from food. Including
  linoleate?linolenate, arachidonic acid amount
  unsaturated in plant

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Section I Digestion and absorption of lipids

• digestion
• small intestinebile?pancreatic
  lipase?colipase?phospholipase A2? cholesteryl
  esterase
• product2-monoacylglycerol(MG)?FFA?Cholesterol?lys
  ophospholipid
• absorption

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Absorption
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Monoacylglycerol synthesis Pathway
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Section IITriacylglycerol metabolism
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Chemical Structure of Triacylglycerol
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Fatty Acid Synthesis

• Palmitic acid synthesis
• Elongation of FA carbon-chainER
• ER
• --Mitochondrial
• Synthesis of Unsaturated FA
• Regulation of unsaturated FA

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Biosynthesis of palmitic Acid

• Tissuesliver(major site) ?kidney?
• breast?adipose? lung ? brain
• ---Cytosol
• MaterialsAcetyl-CoA?NADPHH?ATP?HCO3- and Mn2
• Pathway
• ---Synthesis of malonyl-CoA
• ---Synthesis of fatty acid

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Citrate Pyruvate Cycle
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malonyl-CoA Synthesis
???
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• The overall reaction, which is spontaneous, may
  be summarized as
• HCO3- ATP acetyl-CoA ? ADP Pi malonyl-CoA

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• Acetyl-CoA Carboxylase, which converts acetyl-CoA
  to malonyl-CoA, is the committed step of the
  fatty acid synthesis pathway.
• The mammalian enzyme is regulated, by
• phosphorylation
• allosteric control by local metabolites.
• Conformational changes associated with
  regulation
• In the active conformation, Acetyl-CoA
  Carboxylase associates to form multimeric
  filamentous complexes.
• Transition to the inactive conformation is
  associated with dissociation to yield the
  monomeric form of the enzyme (protomer).

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AMP-Activated Kinase catalyzes phosphorylation of
Acetyl-CoA Carboxylase, causing inhibition.

• The decreased production of malonyl-CoA prevents
  energy-utilizing fatty acid synthesis when
  cellular energy stores are depleted. (AMP is
  abundant only when ATP has been extensively
  dephosphorylated.)

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• The antagonistic effect of insulin, produced when
  blood glucose is high, is attributed to
  activation of Protein Phosphatase.

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Regulation of Acetyl-CoA Carboxylase by local
metabolites

• Palmitoyl-CoA (product of Fatty Acid Synthase)
  promotes the inactive conformation, diminishing
  production of malonyl-CoA, the precursor of fatty
  acid synthesis.
• This is an example of feedback inhibition.

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Citrate allosterically activates Acetyl-CoA
Carboxylase.

• Citrate is high when there is adequate
  acetyl-CoA entering Krebs Cycle.
• Excess acetyl-CoA is then converted via
  malonyl-CoA to fatty acids for storage.

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• Fatty acid synthesis from acetyl-CoA
  malonyl-CoA occurs by a series of reactions that
  are
• in bacteria catalyzed by 6 different enzymes plus
  a separate acyl carrier protein (ACP)
• in mammals catalyzed by individual domains of a
  very large polypeptide that includes an ACP
  domain.
• NADPH serves as electron donor in the two
  reactions involving substrate reduction.
• The NADPH is produced mainly by the Pentose
  Phosphate Pathway.

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Mammalian fatty acid synthase

• A dimer of two polypeptides of 240 kDa each
• Each polypeptide contains eight domains that
  represent the seven catalytic centres plus an
  integral acyl carrier protein (ACP) domain

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4' phosphopantetheine
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The structure of the mammalian Fatty Acid
Synthase protein is summarized aboveKS
b-Ketoacyl Synthase (Condensing
Enzyme)---(Cys)AT Acyl transferaseMT
Malonyl/Acetyl-CoA Transacylase DH
DehydrataseER Enoyl Reductase KR b-Ketoacyl
Reductase TE Thioesterase ACP Acyl Carrier
Protein ---(Pant)
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4. Reduction
5. Acyl transfer
3.Dehydration
1.Condensation
2.Reduction
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• Elongation of FA Carbon-chain
• ER
• Mitochondria
• Synthesis of unsaturated FA
• unsaturated FA ????Oleate?linoleate?linolenate?ar
  achidonic acid ( Essential FA )
• Essential FArequired for the growth of mammals
  and they must be obtained from food. Including
  linoleate?linolenate, arachidonic acid

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????
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Regulation of FA synthesis

• Dietary factors carbohydrate promotes synthesis
• Hormone factors
• insulin,store hormone,increase FA synthesis
• Glucagon ,release hormon,inhibit FA
  synthesis

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Important of polyunsaturated fatty
acids---prostaglandins (PG)? thromboxanes (TX)?
leukotrienes (LT)

• Chemical structure and nomenclature of PG? TX? LT
• Synthesis of PG?TX and LT
• Physiological functions of PG?TX and LT

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Thromboxane A2
Leukotriene A4(LTA4)
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Synthesis of PG?TX and LT
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Physiological functions of PG?TX and LT

• PGPGE2 triggers inflammationPGE2?PGA2
  downregulates blood pressurePGF2promotes
  ovulation?delivery
• TXTXA2 and PGE2 promotes coagulation and
  thrombosis
• PGI2inhibiting coagulation and thrombosis
• LTConstriction of bronchial smooth muscle
  cells,Slow reaction substances(SRS-A)are mixtures
  of LTC4?LTD4and LTE4

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?????

• ??????????????????????????????
• ?????????????????????????????????

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Synthesis of Triglycerideslocation
liver?adipose tissue and small
intestinal materialsglucose?dietary
fatspathwayAcylglycerol pathway
diacylglycerol pathway
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Dietary (external)
Fat synthesis(internal)
CM
FFA
CM
VLDL
FFA mobilization
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Diacylglycerol Pathway
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Degradation of Triacylglycerols

• Lipolysis
• Glycerol Metabolism
• ß-Oxidation
• Other oxydation modes of fatty acid
• Formation and utilization of Ketone Bodies

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Lipolysis

• Concept
• Committed enzymehormone-sensitive triglyceride
  
• lipase (HSL)
• Lipolysis hormonesadrenalin ?glucagon?ACTH and
  TSH
• Anti-lipolysis hormonesInsulin?PEGE2 and
  Nicotinic Acid

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PPi
ADP
HSL (active)
HSL (inactive)
P
Pi
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Glucagon
Insulin
Committed enzyme
()
(-)
ATP
HSL
adenylyl cyclase
()
cAMP
Protein kinase
TG
DG
FFA
lipolysis
MG
FFA
glycerol
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Glycerol metabolism
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Experimental evidence for ß-Oxidation of fatty
acid
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ß-Oxidation of fatty acid

• ???????????ß-?????,???????????(acetyl-CoA)
• StepsActivation of FAenter into mitochondria
• ß-oxidation TAC(Tricarboxylic acid
  cycle)

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Activation of fatty acid Formation of Acyl-CoA

• Locationcytosol

acyl-CoA
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Carnitine
(Acyl-CoA)
(Carnitine)
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Mitochondrion
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Carnitine acyltransferase ?
???
CoASH
Carnitine acyltransferase ?
CoASH
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Acyl CoA enter into mitochondrion
Committed enzyme
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ß-Oxidation of fatty acid

• locationmitochondrial matrix
• ??????ß-???????????,????ß?????,dehydrogenation
  ???hydration?dehydrogenation ?thiolysis??,????????
  ?????????CoA(acyl-CoA)??????CoA(acetyl-CoA)

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a
ß
FAD
(dehydrogenation)
FADH
H2O
(hydration)
NAD
(dehydrogenation)
H
NADH
CoASH
(thiolysis)
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(dehydrogenation)
(hydration)
(dehydrogenation)
(thiolysis)
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???ß-Oxidation??

• ?????????(cytosol),????ATP??????
• Acyl-CoA?carnitine?????,???CAT-?
• ß-Oxidation(mitochondrion) including
  dehydrogenation ?hydration ?dehydrogenation
  ?thiolysis four repeated steps

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??????????

• ????(C16)
• 7?ß-??,??8????CoA?7??FADH2?7??NADH
• ? 12 8 273 7131??ATP
• ????????2??????
• ???131-2129??ATP
• formula12 5 ( -1) 2

• ?????

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Difference between synthesis and degradation of
palmitic Acid
difference synthesis degradation
location cytosol mitochondria
Acyl carrier ACP CoA
Two carbon- fragment Malonyl-CoA Acytel-CoA
reducing equivalents NADPH FAD?NAD
HCO3- and citrate needed Not needed
Energy alteration Consume 7ATP14NADPH Form 129ATP
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Difference Between Fatty Acid Synthesis And
ß-Oxidation
Diffference Synthesis ß -Oxidation
Location Cytoplasm Mitochondrion
Thioester linkage ACP CoA
Two carbon-fragment Malonyl-CoA Acetyl-CoA
Electron carrier NADPH FADH?NADH
HCO3- and cytratre needed Nod needed
Energy alteration Consume 7ATP14NADPH Form 129ATP
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Other oxydation modes of fatty acid

• Oxydation of unsaturated FA
• FA oxydation in peroxisomes
• Oxydation of propionic acid

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Formation and utilization of Ketone Bodies

• Ketone BodiesAcetoacetate? ß-Hydroxybutyrate and
  Acetone
• Ketogenesis
• Utilization of Ketone Bodies
• Physiology Significance of Ketogenesis
• Regulation of Ketogenesis

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ketone bodies(KB)
a
ß
?
ß-hydroxybutyrate
Acetoacetate
Acetone
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CoASH
CoASH
???
CoASH
a
ß
NAD
CO2
NADH
H
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Formation of Ketone Bodies
???
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Utilization of Ketone Bodies
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Liver Blood
Extrahepatic Tissues
?
?
Urine
?
?
?
Citric acid cycle
?
?
Citric acid cycle
Acetone Lungs
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Major energy materials provided for tissues
Glucose FFA KB
Red Blood Cell
Brain
Muscle (exercise) (rest)
Liver
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Concentration of energy materials of the blood in
full of eating or hungry (mmol/L)
Full(of eating) Hungry(5-6 weeks)
Glucose 5.0 4.49
ß-Hydroxybutyrate 0.02 6.67
Acetoacetate 1.17
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Physiology Significance of Ketogenesis

• Ketone bodies serve as a fuel for extrohepatic
  tissues.
• Ketoacidosis results from prolonged
  ketosisHigher than normal quantities of ketone
  bodies present in the blood or urine constitude
  ketonemia or ketonuria, respectively.The overall
  condition is called ketosis.

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Three Crucial Steps for Ketogenesis Regulation

• Control of free fatty acid(FFA) mobilization from
  adipose tissue
• The activity of carnitine acyltransferase (CAT-1)
  in liver,which determines the propotion of the
  fatty acid flux that is oxidized rather than
  esterified
• Partition of acetyl-CoA between the pathway of
  ketogenesis and the citric acid cycle

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Regulation of Ketogenesis
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???

• ????
• 1??????(lipolysis)
• 2?????????????(HSL)
• 3?????
• 4?????ß-??(ß-oxidation)
• 5?????(essential fatty acid)
• 6???(ketone bodies)

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• ??
• 1?????????????
• 2?????????????
• 3???????????????
• 4???????????????CO2?H2O,??????ATP????????????

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???

• 1?????? ? ? ? ? ? ? ? ? ?
• A? ? ? ? ? ? ? ? ? ?
• B? ? ? ? ? ? ? ? ? ? ?
• C? ? ? ? ? ? ? ? ? ? ? ?
• D? ? ? ? ? ? ? ? ? ? ? ?
• E? ? ? ? ? ? ? ? ? ? ? ?

(A?B)
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???

• 2?? ? ? ? ? ? ?, ? FAD ? ? ? ? ? ? ?
• A? ? ? ? ? ? ? ? CoA
• B? ß-? ? ? CoA ? ?
• C? ? ? ? ? ? ?
• D? ? ? CoA ? ?
• E? ß-? ? ? ? ?

(D)
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???

• 3????14 ???????ß-?????CoA
• A?????????2 ???????
• B???????7?ß-?????7????CoA
• C???6 ??FADH2 ?6 ??NADH H
• D??????????????ß-??????

(A?C)
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???

• 4??????????????????????
• A?????? B???CH3COCoA
• C?ß????????RCH2CH2CH2COCoA
• D???????RCH2CHOHCH2COCoA
• E??????NAD?NADH

(A)
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???

• 5?????1?????CoA(180)????????O2?
• A?23 B?26 C?30
• D?16 E?32

(B)
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???
(A?B?C?D)

• 6???????????
• A?????????????ß-???
• B??????????
• C??????????
• D???????????

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???

• 7????????CO2?H2O????
• A??? B????
• C?? D??

(A?C)
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• ?????
• ??????????????????????????????
• ?????????????????????

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Section IIPhospholipid Metabolism
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Classification of Phospholipids

• phosphoglyceride
• Phosphatidylcholine (PC)
• Phosphatidylethanolamine (PE)
• Phosphatidylserine (PS)
• Phosphatidylglycerol (PG)
• Diphosphatidylglycerol (DPG)
• phosphatidyl inositol(PI)
• Sphingomyelin

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• Chemical Structure of Phosphoglyceride

Most phospholipids have a saturated fatty acid on
C-1 and an unsaturated fatty acid (Arachidonic
Acid )on C-2 of the glycerol backbone.
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Structure of Phospholipid
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Classification of phosphoglyceride-1

• X-OH X-
  name

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Classification of phosphoglyceride-2
X-OH X-
name
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Glycerophospholipid synthesis

• Site liver,kidney,intestine
• endoplasmic reticulum, ER
• SourcesFA,glycerol,phosphate,nitrogenous base
  (choline,ethanolamine,serine,inostol,etc),ATP,
  CTP
• CDP- nitrogenous base
• CDP-diacylglycerol

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CDP-choline?CDP- diacylglycerol
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Diacylglycerol Pathway
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Diacylglycerol PathwayPE, PC
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CDP- Diacylglycerol PathwayPI?PS?DPG
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Synthesis of CDP- nitrogenous base
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Phosphoglycerol degradation
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Metabolism of Sphingolipids
Sphingomyelins and Glycosphingolipids
XPhosphorylcholin or phosphoethanolamine
XMono-or Poly- saccharin
Sphingomyelin
Glycosphingolipid
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Synthesis and Degradation of
Sphingomyelin

• Site brain---ER
• Soucespalmitoyl-CoA,
• Serine,NADPHH,FAD
• Pathway

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Degradation of Sphingomyelin

• Sphingomyelinase (PLC )
• -----Defects in the enzymes
  result in
• genetic diseases such as
  Niemann-
• Pick disease

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?????

• ????????????????????CTP????????????????

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???

• 1?????????(??)
• ??????????,????????????
• ???????????????
• 2?????????????????????????(??)
• 3??????????????????
• 4????????????????

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???

• ????1?????CoA(180)????????O2?
• A?23 B?26 C?30
• D?16 E?32

(B)
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???

• 1????????????????
• A?????CoA
• B?????????CoA
• C????????
• D??NADH????
• E????????????

(B)
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???

• 2??????????CoA?
• A???????
• B??????????????????
• C???????????
• D??????,???CoA???
• E??????????

(B)
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???

• 3??????????????
• A???? B????
• C???? D????

(B)
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???

• 4???????????????
• A?TDP-?? B?ADP-??
• C?UDP-?? D?GDP-??
• E?CDP-??

(E)
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Section IV Cholesterol(Ch) Metabolism
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Cholesterol Structure
Cholesterol(Ch)
Cholesterol Ester(CE)
??????
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Roles of Cholesterol

• Membrane component
• Steroid synthesis
• Bile acid/salt precursor
• Vitamin D precursor

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Sources of Cholesterol
Cholesterol synthesized in extrahepatic tissues
De novo synthesis
Diet
Liver cholesterol pool
Free cholesterol In bile
Conversion to bile salts/acids
Secretion of HDL and VLDL
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Dietary Cholesterol

• Animal products eggs
• Absorb about 50
• Increase intake decreased absorption
• Excrete 1 g/day (bile acids)

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Dietary Cholesterol

• Assume 400 mg intake / day
• 200 mg is absorbed
• 1000 mg is excreted
• 800 mg from de novo synthesis
• Lowering cholesterol in diet has very little
  effect on blood cholesterol !!!

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Cholesterol Synthesis

• 80 in liver, 10 intestine, 5 skin
• Occurs in cytosol
• Requires 18Acetyl-CoA?16NADPH?36ATP
• Similar to ketogenic pathway
• Highly regulated

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Cholesterol Synthesis-1
???
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Cholesterol Synthesis -2
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Cholesterol Synthesis Summary
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Regulation of Cholesterol Synthesis

• rate-limiting enzymeHMGCoA reductase
• Regulation factors
• Famine and saturation famine (-), fasting (-)
• cholesterol inactivate HMGCoA reductase
• Hormons insulin/thyroxin induce activity of
  HMGCoA reductase glucagon/cortisol/Epi
  inactivate HMGCoA reductase

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HMG CoA reductase - Phosphorylation
HMG CoA reductase OH (active)
HMG CoA reductase P (inactive)
AMP-Activated Protein Kinase (high
activity)
()
AMP
phosphatase
kinase
()
()
AMP-Activated Protein Kinase (low activity)
increase cAMP
Insulin
Glucagon/epi
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Conversion of Cholesterol

• Bile acid liver (2/5)
• Steroids adrenal cortex, testicle,ovary
• Vitamin D skin(7-dehydrocholeterol and
• Vitamin D3)

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?????

• ????????????????????????????????????
• ????????????????????????????

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Section IV Metabolism of Plasma Lipoproteins

• Plasma lipids
• Plasma lipoproteins
• Apolipoproteins
• Metabolism of Plasma Lipoproteins
• Medical implications

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• Plasma Lipids ----Lipids in plasma
• TG100mg/dl
• PL 200mg /dl
• lecithins
  70
• nerve sphingomyelin 20
• cephalin
  10
• Ch and CE200mg /dl
• Ch55mg /dl CE145mg /dl
• FFA15mg /dl
• Origin of plasma lipids
• Exogenous dietary lipids
• Endogenous synthetized by liver, adipose
  tissue and
• other tissues

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Plasma Lipoproteins

• Classes
• electrophoresisCM (Chylomicron) ?ß? pro-ß?a
• ultracentrifugation
• CM?VLDL(very low density lipoprotein)?LDL?HDL

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Compositions of plasma lipoproteins
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Structure of plasma lipoprotein
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Apolipoproteins (apo) -1
Type Association Function
B48 Chylomicron Carry cholesterol
esters Lacks LDL recpt binding
domain B100 VLDL,IDL,LDL Binds LDL
recpt. C-II Chyl. VLDL, IDL, HDL Activates
LPL C-III Chyl. VLDL, IDL, HDL
Inhibits LPL E Chyl. Remnant,
VLDL, IDL Binds LDL recpt HDL A-1 HDL/Chyl
omicron LCAT activator (lecithincholestero
l acyltransferase) A?
HDL
HL()??HDL A?
HDL,CM
LPL()
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Apolipoprotein (apo) -2
Type Association Function
D HDL
transports CE J
HDL binds and transports
lipids CETP HDL
transports CE,TG PTP
HDL transports PL
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Major Enzymes for Lipoprotein Metabolism

• lipoprotein lipase,LPL
• hepatic lipase,HL
• lecithin cholesterol acyltransferase, LCAT
• acyl-CoA cholesterol acyltransferase, ACAT

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lipoprotein lipase,LPL

• hepatic lipase,HP

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lecithin cholesterol acyltransferase, LCAT
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acyl-CoA cholesterol acyltransferase,ACAT
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CM Metabolism
apoC???LPL
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VLDL Metabolism
apoC???LPL
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CE
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LDL Metabolism
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HDL Metabolism
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Function of plasma lipoproteins

• CMTransport dietary from intestine to
• liver (exogenous)
• VLDL Transport lipids from liver to peripheral
  
• tissues (endogenous
• LDLendogenous Cholesterol transport
• HDLreverse Cholesterol transport

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Clinical importance for disease

• Hypertriglyceridemia and CHD Risk Associated
  Abnormalities
• Accumulation of chylomicron remnants
• Accumulation of VLDL remnants
• Generation of small, dense LDL
• Association with low HDL
• Increased coagulability
• - ? plasminogen activator inhibitor (PAI-1)
• - ? factor VIIc
• - Activation of prothrombin to thrombin

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Genetic Disease

• LPL Deficiency
• LDL receptor Deficiency

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?????

• ????????????????????????????
• ????????????????LDL???????????????????

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???

• ??????
• 1???2??????3?????
• ????
• 1????????????
• 2???????????(?????????)?????????

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????? ???
154
1. ?????????( )
A ????????(HSL) B ??? C ?????? D ????? E ???
155
2. ??????????????( )
A ????? B ???? C ACTH D ????? E ???
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3. ????????????,??????????( )
A ??? B ?? C ?? D ??? E ???
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4. ????????????( )
A ??CoA??? B ???????I C ???????II D
??CoA??? E ?-????
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5. ??????-??????????( )
A ??,??,???,?? B ??,??,???,?? C ??,???,??,
?? D ??,??,??,??? E ??,??,??,???
159
6. ?????,???????????( )
A ???? B ?????? C ?????? D ???? E ????
160
7. ?????????????( )
A ??? B ??? C ??? D ???? E ??
161
8. ????HMG-CoA????????????( )
A ?????????? B ????????????? C ??????????? D
?????????? E ???????????
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9. ?????????????????????( )
A ??????B B ?VLDL??LDL?? C ???LDL?????? D
??HMG-CoA??????? E ??????????(ACAT)????
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10. ????????????????( )
A ????????????? B ?????????????????CoA C
???????? D ??ATP E ??NADPH??
164
11. The organ having the strongest ability of
fatty acid synthesis is ( )
A fatty tissue B lacteal gland C liver D
kidney E brain
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12. Which one transports cholesterol from outer
to inner of liver?
A CM B VLDL C LDL D HDL E IDL
166
13. Which one is essential fatty acid?
A palmitic acid B stearic acid C oleinic acid D
octadecadienoic acid E eicosanoic acid
167
14. The main metabolic outlet of body
cholesterol is ( )
A change into cholesterol ester B change into
vitamine D3 C change into bile acid D change
into steroid hormone E change into
dihydrocholesterol
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15. ????????????????( )
A ??? B ?????? C ???????? D ??? E ??

169
16. ??????????????( )
A ?? B ??? C ?? D ??? E ???
170
17. ?????????????( )
A ????????(HSL) B ??????(LPL) C ????(HL) D
???????????(LCAT) E ???????????(ACAT)

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18. ???????( )

A ???????? B ?????????????? C ???????? D CM
VLDL?????????? E LDL HDL??????????
172
19. Which can be the source of acetyl CoA?

A glucose B fatty acid C ketone body D
cholesterol E citric acid
173
20. The matters which join in synthesis of
cholesterol directly are ( )
A acetyl CoA B malonyl CoA C ATP D NADH E
NADPH