chapter 5. metabolism of lipids lipids insoluble or immiscible triacylgerols store and supply energy...
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Chapter 5.Metabolism of Lipids
Lipids
Insoluble or immiscible
Triacylgerols
store and supply energy for metabolism. Lipoids: phospholids, glycolipids, cholesterol and
cholesterol ester
membrane components
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Metabolism of lipid Fatty acids
esterified to some backbone molecules
glycerol sphingosine
cholesterol
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Metabolism of Lipids Fats
store in adipose tissue
Essential fatty acids: formation of membrane, regulation of chollesterol metabolism, precursors of eicosanoids (protaglandins, thromboxanes and leukotrienes.
Necessary unsaturated fatty acids
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Fat Facts Dietary lipids are 90% triacylglycerols; also include
cholesterol esters, phospholipids, essential unsaturated fatty acids; fat soluble vitamins (A,D,E,K)
Fat is energy rich and provides 9 kcal/gm
Normally essentially all (98%) of the fat consumed is absorbed, and most is transported to adipose for storage.
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SIX STEPS OF LIPID DIGESTION AND ABSORPTION
Minor digestion of triacylglycerols in mouth and stomach by lingual (acid-stable) lipase
Major digestion of all lipids in the lumen of the duodenum/jejunum by pancreatic lipolytic enzymes
Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic bile acid recycling
Assembly and export from intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids
Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell
Reesterification of 2-monoacylglycerol, lysolecithin, and cholesterol with free fatty acids inside the intestinal enterocyte
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Lipase Site of Action
Regulation Preferred Substrate
Ccleaved
Product(s)
lingual/acid-stable lipase
mouth, stomach
---- TAGs with med. chain FAs
3 FFA+DAG
pancreatic lipase
small intestine
colipase (+) TAGs with long-chain FAs
1 and 3 FFA+2MG
milk lipase small intestine
bile acids (+) TAGs with med. chain FAs
1 and 2 and 3
FFA+glycerol
phospholipase A2 (PLA2)
small intestine
bile acids (+) Ca2+ (+)
PLs with unsat. FA on position 2
2 Unsat FFA lysolecithin
lipoprotein lipase
capillary walls
apo CII (+)insulin (+)
TAGs in chylo-micron or VLDL
1 and 2 and 3
FFA+glycerol
Hormone-sens. Lipase
adipose cell insulin (-)glucagon (+)Epineph. (+)
TAG stored in adipose cells
3 FFA+DAG
Summary of the physiologically important lipases
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Absorption of Lipids
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Metabolism of Triacylglyerols
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Mobilization of fats from triacylglycerols
Hormone sensitive lipase
Rate-determining step
Specific for removing first fatty acid
Phosphorylated form is active
LIPOLYSIS
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RECEPTORS
ATP
proteinkinase A
cellmembrane
EpinephrineGlucagon
HORMONES
cyclicAMP
ATP
ADP
= activation- = inhibition
TriacylglycerolFatty acid +
Diacylglycerol
OPHSL-a
HSL = hormone-sensitive lipase
proteinphosphatase
Pi
+ Insulin
- caffeinetheophylline
phosphodiesterase
AMP
+
Figure 1. Hormonal activation of triacylglycerol (hormone-sensitive) lipase. Phosphorylation brings about activation to HSL-a.
Adenylylcyclase
(inactive form)
HSL-bOH
inactive
active
+
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lipolysis Glycerols and fatty acids
diffuse out of adipose cells and enter into circulation
Free fatty acids (FFA)
form fatty acid-albumin complexes Glycerols
to form dihydroxyacetone phosphate (DHAP)
Figure. Page 176
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Beta-Oxidation of Fatty Acids
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Beta Oxidation Part IThe break down of a fatty acid to acetyl-CoA
units…the ‘glycolysis’ of fatty acids
Occurs in the mitochondria
Exemplifies Aerobic Metabolism
at its most powerful phase
STRICTLY AEROBIC
Acetyl-CoA is fed directly into the Krebs cycle
Overproduction causes KETOSIS
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CH3CH2CH2COOH
[CH3CH2CH2CO-AMP]
CH3CH2CH2CO~SCoA
HS-CoA
Fatty acyl CoA
ATP
PPi
AMPAcyl-CoA synthetase
Prepares a Fatty Acid for transport and metabolism
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CH2CH2CH2COO CH2CH2COO
OCH2CO COO
Diet
Urine
(even chain) (odd chain)
Phenylpyruvate Benzoate
Knoop’s Experiment
Phenylacetate Benzoate
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Beta-Oxidation of Fatty Acids
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C6H12O6 + 6O2 6CO2 + 6H2O Ho = -2,813 kJ/mol = - 672 Cal/mol = 3.74 Cal/gram
C18H36O2 + 26O2 18CO2 + 18 H2O Ho = -11,441 kJ/mol = - 2,737 Cal/mol = 9.64 Cal/gram
THE ENERGY STORY
Glucose
Stearic Acid
On a per mole basis a typical fatty acid is 4 times more energy rich that a typical hexose
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Sample calculation of energy produced for the cell via -oxidation of palmitate (a C16 fatty acid):
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Palmitoyl-CoA
Palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ + 7H2O
8 Acetyl-CoA 80 ATP
7 FADH2 10.5 ATP
7 NADH + 7H+ 17.5 ATP
108 ATP-2 ATPTotal 106 ATP
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Beta Oxidation Part II
Unsaturated fatty acid
Polyunsaturated fatty acid
Odd number chain fatty acid
Obstacle of cis double bonds
Obstacle of position of double bond
Obstacle of 3 carbons at the end
3 Obstacles
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CH3CH2CH2CH2CH2C CH2CH2CH2CH2CH2CH2CH2CO~SCoAC=C
HH4 3 2 1
Whoops!A cis D.B. will interfere
Oleic Acid
CH3CH2CH2CH2 CH2 CH2CH2CH2CH2CH2CH2CH2CO~SCoAC=C
HHC=C
HH12345
Linoleic
C18:cis9
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Unsaturated and Polyunsaturated Require Additional Enzymes
H H
CH3CH2CH2
C=CCH2CH2CH2-CO~SCoA
Cleavage here
New COO group
New carbon
8 7
CH3CH2CH2
CH2C C-CO~SCoA
H
H
8 7
Enoyl CoAIsomerase
9
9
Trans double bond
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CH2-CH2
C=C
CH2
C=C
CH2-CH2-CH2-CH2-CH2-CH2CH2C~SCoA
O
H 9HHH
O
CH2C~SCoA
O
CH2C~SCoAO
CH2C~SCoA
1234
O
CH3C~SCoA12
O
CH3C~SCoA34
O
CH3C~SCoA56
Linoleic Acid C18 cis 9,12
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Poly Unsaturated (Continued)
9
-CH2 CH2 CH2CO~SCoAC=CH H
C=CH H
-CH2 CH2 C-CO~SCoAC-CH H
C=CH H
H
-CH2 CH2
CH2CO~SCoAC=CH H
Enoyl-CoAisomerase
Round 5starter
Round 4starter
Beta carbon to be
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Round 5starter
FADH2
FAD
CO~SCoAC=CH H
CH2
Dead end
Acyl-CoAdehydrogenase
Acyl-CoAdehydrogenase
-CH2 CH2
CH2CO~SCoAC=CH H
New Strategy
C-CO~SCoAC
C=CH H
H
H
beta 6
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NADP+
NADPH + H+
2,4 dienoyl-CoAreductase
2,4 dienoyl-CoAreductase
3,2 enoyl-CoAisomerase
3,2 enoyl-CoAisomerase
CH2CO~SCoA H
CCCH2
H
Continue Beta Oxidation
Reduce near (bond), Shift far (bond)
C-CO~SCoAC
C=CH H
H
H
beta 6
beta 6
H
C-CO~SCoA C
CH2-CH2
H
beta 6
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Ketone bodies formation and utilization
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What is Ketosis?An excessive production of ketones in the blood
3 derivatives of acetyl-CoA
Acetoacetate
-hydroxybutyrate
Acetone
CH3CCH2COO-
O
O
CH3-C-CH3
CH3CCH2COO-
OH
H
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What is the Significance of ketosis
Acidosis
Excessive acid in the blood
Overflow
Excessive oxidation of fatty acids
Faulty Carbohydrate Metabolism
Metabolic Problem
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Metabolic fate of Acetyl CoA
Acetyl-CoA
Pyruvate
Citrate
Ketone BodiesFatty Acidsminor
major
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CH3C~SCoA
OCH3C~SCoA
O
-Ketothiolase
HS-CoA
CH3C
CH2C~SCoA
O
OH
+
CH3CCH2C~SCoA
O O
rearrangement
Acetoacetyl-CoA
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CH3CCH2C~SCoA
O OCH3C~SCoA
O
CH3CCH2C~SCoA
CH2C-O-
O
OHO
HS-CoA
OOC-CH2-C-CH2-C~SCoA
O
OH
CH3
HMG-CoASynthase
-hydroxy--methylglutaryl-CoA
(HMG-CoA)
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OOC-CH2-C-CH2-C~SCoA
O
OH
CH3
O
OOC-CH2-C-CH2-C~SCoA
OH
CH3
CH3-C~SCoA
O+
OOC-CH2-C-CH3
O
CH3-C-CH3
O
CO2
OOC-CH2-CH-CH3
OH
NADH + H+
NAD+
Acetoacetate
Acetone-hydroxybutyrate
HMG-CoA
HMG-CoALyase
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Utilization of ketone bodies
1. Acetoacetate/succinyl-CoA CoA transferase
2. Acetoacetyl-CoA thiokinase
3. Acetoacetyl-CoA thiolase
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Pysiological Significance of ketogenesis
Ketone bodies produced by the liver are excellent fuels for a variety of extrahepatic tissues, especially during times of prolonged starvation.
Reconversion of ketone bodies to acetyl-CoA inside the mitochondria provides metabolic energy.
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Regulation of Ketogenesis
Feeding status In the hungry state, higher glucagon and other
lipolytic hormones trigger the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. This promotes fatty acid oxidation and ketogenesis in the liver.
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Regulation of Ketogenesis Metabolism of glycogen in the hepatic cells
once fats enter the liver, they have two distinct fates: activated to acyl-Co-A and oxidized, or esterified to glycerol in the production of triacylglycerols in cytoplasm. If the liver has sufficient supplies of glycerol-3 phosphate by glucose metabolism, most of the fats will be turned to the production of triacylglycerols. In contrast, glucose deficiency will cause a lower triacylglycerols and ATP generation, with the majority of the FAs entering beta-oxidation leading to a increased production of ketone bodies.
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Regulation of Ketogenesis The fall in malonyl-CoA concentration can terminate
the inhibition on carnitine acyltransferase I, such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. This may happen during a hungry state. In contrast, administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations and increases liver concentration of malonyl-CoA, this will inhibit carnitine acyltransferase I and thus reverses the ketogenic process.
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Fatty Acid Biosynthesis Not exactly the reverse of degradation
by a different set of enzymes , in a different part of the cell
Primarily in the cytoplasm of the following tissues: liver, kidney, adipose, central nervous system and lactating mammary gland
Liver is the major organ for fatty acid synthesis
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LIPID BIOSYNTHESIS Fatty acid biosynthesis-basic fundamentals Fatty acid biosynthesis-elongation and
desaturation Triacylglycerols Phospholipids Cholesterol Cholesterol metabolism
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Fatty Acid Biosynthesis
Cytosol Requires NADPH Acyl carrier protein D-isomer CO2 activation
Keto saturated
Mitochondria NADH, FADH2
CoA L-isomer No CO2
Saturated keto
Beta OxidationSynthesis
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Rule:
Fatty acid biosynthesis is a stepwise assemblyof acetyl-CoA units (mostly as malonyl-CoA) ending with palmitate (C16 saturated)
Fatty acid biosynthesis is a stepwise assemblyof acetyl-CoA units (mostly as malonyl-CoA) ending with palmitate (C16 saturated)
Activation
Elongation
Termination
3 Phases
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CH3C~SCoA
O
ACTIVATION
-OOC-CH2C~SCoA
O
HCO3-
NN
O
SCH2CH2CH2CH2CO
HH
LYS
NHCH2CH2CH2CH2 ENZYME
NN
O
SCH2CH2CH2CH2CO
HC
O
O
Carboxybiocytin
Biotin
active carbon
Acetyl-CoA carboxylase
CO2
Biocytin
Cofactor
ATP
ADP + Pi
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Acetyl-CoA CarboxylaseThe rate-controlling enzyme of FA synthesis
In Bacteria -3 proteins (1) Carrier protein with Biotin (2) Biotin carboxylase (3) Transcarboxylase
In Eukaryotes - 1 protein (1) Single protein, 2 identical polypeptide chains
(2) Each chain Mwt = 230,000 (230 kDa)(3) Dimer inactive (4)
Activated by citrate which forms filamentous form of protein that can be seen in the electron microscope
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Yeast Fatty Acid Synthase Complex
2,500 kDa Multienzyme Complex
6 molecules of 2 peptide chains called A and B
(66)A: (185,000) Acyl Carrier protein -ketoacyl-ACP synthase (condensing enzyme) -ketoacyl-ACP reductase
B: (175,000) -hydroxy-ACP dehydrase enoyl-ACP reductase palmitoyl thioesterase
Fatty AcidSynthaseComplex
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Acyl carrier protein10 kDa
Cysteamine
Phosphopantetheine
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2
O O O
OH H
H
HO CH3
H
O
OO Adenine
O-P-OO
OH
OHH
Coenzyme A
Acyl Carrier ProteinAcyl Carrier Protein
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser-O O O
OH H
H
HO CH3
H
ACP
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Overall Reaction
CH3C~SCoA
O
CH3C-
O
CH2C~S-
O
ACP
HS-CoACO2
NOTE:
Malonyl-CoA carbons become new COOH end
Nascent chain remains tethered to ACP
Acyl CarrierProtein
CO2, HS-CoA are released at each condensation
Malonyl-CoA + ACP
-OOC-CH2C~S-
O
ACP + HS-CoA
Initiation
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CH3C-
O
CH2C~S-
O
ACP
NADPH
CH3CH2CH2C~S-
O
ACP
CH3C- CH2C~S-
O
ACP
HO
H
CH3C- = C- C~S-
O
ACPH
H
-H2O
NADPH
-Carbon Elongation
D isomer
Reduction
Dehydration
Reduction
-Ketoacyl-ACP reductase
-Hydroxyacyl-ACP dehydrase
Enoyl-ACP reductase
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-KS
CO2
-S-ACP
TERMINATION Ketoacyl ACPSynthase
Free to bindMalonyl-CoA
Transfer to KS
Split out CO2
Transfer to Malonyl-CoA
-CH2CH2CH2C~S-
O
ACP
When C16 stage is reached, instead of transferring to KS,the transfer is to H2O and the fatty acid is released
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ACP
KS -SH
HSAcetyl-CoA
CoA-SH
-C-CH3
OS
KS S-C-CH3
OKS -SH
SH
CoA-SH
Malonyl-CoA
S -C-CH2-COO-
O
CO2C=O
CH2
C=O
CH3
S
O
CH3-CH -CH2-C-S
OH
OCH3-CH=CH-C-S
OCH3-CH2-CH2-C-S
S-C-CH2-CH2-CH3
O
KS
KS
NADP+
NADPH H+
NADPH H+
NADP+
H2O
Initiation or priming
Elongation
Fatty Acid SynthaseFatty Acid Synthase
-Ketoacyl-ACP reductase
-Ketoacyl-ACP reductase
-Hydroxyacyl-ACP dehydrase
-Hydroxyacyl-ACP dehydrase
Enoyl-ACP reductase
Enoyl-ACP reductase
-Keto-ACP synthase (condensing enzyme)
-Keto-ACP synthase (condensing enzyme)
Malonyl-CoA-ACP transacylase
Malonyl-CoA-ACP transacylase
Acetyl-CoA-ACP transacylase
Acetyl-CoA-ACP transacylase
-Ketoacyl-ACP synthase
-Ketoacyl-ACP synthase
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Overall ReactionsAcetyl-CoA + 7 malonyl-CoA + 14NADPH + 14H+
Palmitate + 7CO2 + 14NADP+ + 8 HSCoA + 6H2O
7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA +7ADP + 7Pi + 7H+
8 Acetyl-CoA + 14NADPH + 7H+ + 7ATP Palmitate + 14NADP+ + 8 HSCoA + 6H2O + 7ADP + 7P
i
7H+
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PROBLEM:
Fatty acid biosynthesis takes place in thecytosol. Acetyl-CoA is mainly in the
Mitochondria
How is acetyl-CoA made available to the cytosolicfatty acyl synthase?
SOLUTION:
Acetyl-CoA is delivered to cytosol from the mitochondria as CITRATE
acetyl-CoA
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COO
COO
HO-C-COO
CH2
CH2
COO
COO
HO-C-COO
CH2
CH2
Citrate lyase
Acetyl-CoA
COO
COOCH2
C=O
COO
COOCH2
HO-C-H
NADH
OAA
L-malate
C=OCOO
CH3
NADP+
NADPH + H+
L-malate
mitochondria
CytosolPyruvate
Malic enzymeOAA
Acetyl-CoACO2
PyrCO2
Malatedehydrogenase
HS-CoA
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Post-Synthesis Modifications
C16 satd fatty acid (Palmitate) is the product Elongation Unsaturation Incorporation into triacylglycerols Incorporation into acylglycerol phosphates
C16 satd fatty acid (Palmitate) is the product Elongation Unsaturation Incorporation into triacylglycerols Incorporation into acylglycerol phosphates
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Elongation of Chain (two systems)
HS-CoA
R-CH2CH2CH2C~SCoAO
OOC-CH2C~SCoA
OCO2
Malonyl-CoA* (cytosol)
R-CH2CH2CH2CCH2C~SCoAO O
O R-CH2CH2CH2CH2CH2C~SCoA
NADPH NADH
1
- H2O2
NADPH3
Elongation systems arefound in smooth ER andmitochondria
CH3C~SCoA
OAcetyl-CoA(mitochondria)
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DesaturationRules:The fatty acid desaturation system is in the smooth membranes of the endoplasmicreticulum
There are 4 fatty acyl desaturase enzymes in mammals designated 9 , 6, 5, and 4 fattyacyl-CoA desaturase
Mammals cannot incorporate a double bondbeyond 9; plants can.
Mammals can synthesize long chain unsaturated fatty acids using desaturation and elongation
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Triacylglycerol Synthesis Fatty acyl-CoA DHAP reduction to glycerol-PO4
or
Glycerol kinase to glycerol-PO4
Two esterifications Diacylglycerol-PO4 intermediate
Triacylglycerol
O-C-RO
O-C-RO
R-C-OO
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CH2O-C-R
R-C-O-C-HCH2OP
O
O
CH2OH
CH2OPC=O
CH2OH
HO-C-HCH2OH
CH2OH
HO-C-HCH2OP
ADP ATP
glycolysis
NADH + NAD+
Glycerol-PO4
glycerol kinase glycerol-PO4
dehydrogenase
Phospholipidbiosynthesis
CH2O-C-R
R-C-O-C-HCH2O-C-R
O
OO
H2O
PO4
CH2O-C-R
R-C-O-C-HCH2OH
O
O
1,2 Diacylglycerol (DAG)
Triacylglycerol Biosynthesis
Not in adiposetissueR-C~CoA
O
2
R-C~CoA
OPhosphatidic acid
DHAP
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Question Can a triacylglycerol (triglyceride) storage
fat be synthesized entirely from glucose, i.e., every carbon in the fat comes from a sugar?
Answer: YES
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Metabolism of Phospholipids Phospholipid
phosphorous-containing lipids
fatty acids, a phosphate group, and a simple organic molecule
Glycerolphospholipids (phosphoglycerides) glycerol Sphingolipid
sphingosine
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Classification of structural features of glycerolphospholipids
Table 8-2
Phospholipids
hydrophilic head , hydrophobic tail
Membrane
phospholipid bilayer
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Glycerolphospholipids
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Phosphatidic Acid
Polar componentEster linkage
- or + = choline, serine, ethanolamine, etc
O
CH2O-C-R
R-C-O-C-HCH2OPO-CH2CH2-N(CH3)3
O
O
O
Phosphatidylcholine or lecithin
PhospholipidBiosynthesis(smooth ER)
- or +O
CH2O-C-R
R-C-O-C-HCH2OP
O
O
O
OO
+
Glycerophospholipids
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Strategy of Glycerophospholipid Biosynthesis Activate diacylglycerol Activate appending moiety (salvage)
N
N
NH2
O
RibosePPP-
CTP
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CH2O-C-R
R-C-O-C-HCH2OP
O
O
Eukaryotes
CH2O-C-R
R-C-O-C-HCH2OH
O
O
Glycerol-3-PO4Glycerol
Phosphatidic acid
1,2 DAG
ATP
choline (CDP-choline)
Glycerol (CDP-diacylglycerol)Serine (phosphatidylethanolamine)
ethanolamine (CDP-ethanolamine)
Inositol (CDP-diacylglycerol)
Cardiolipin (phosphatidylglycerol)
DHAPFA-CoA
1-Acyl-DHAP
1-Acyl-glycerol-3-PO4
NADPH
DAG
1
2
3
ATP
Pi
CDP-diacylglycerolCTP
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P
O
O
O
O
O
P
O
OO
OH
CH2
HO
N
N
O
NH2
CH2CH2(CH3)N3
+
Cytidine diphosphate (CDP) choline
P
O
O
O
O
O
P
O
OO
OH
CH2
HO
N
N
O
NH2
CH2CH2N3+
Cytidine diphosphate (CDP)
H
ethanolamine
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Regulation of Triacylglecerol Metabolism
Pancreas
primary organ involved in sensing the organism’s dietary and energetic states.
monitoring glucose concentrations in the blood. Low blood glucose stimulates the secretion
of glucagon Elevated blood glucose calls for the
secretion of insulin
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Acetaly-CoA carboxylase (ACC) Committed enzyme in fatty acid synthesis
activated by citrate
inhibited by palmitoyl-CoA, long-chain fatty acyl-CoAs
Affected by phosphorylation
glucagon or epinephrine
decreased activity of ACC by phosphorylation
insulin
increases the synthesis of triacylglycerols
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Important Derivatives of Unsaturated Fatty Acids- Arachidonic Acid
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EICOSANOID FACTS
20-carbon compounds
Include prostaglandins, prostacyclins, thromboxanes, leukotrienes
Physiological effects at very low concentrations
Many of their effects mediated by cyclic AMP or calcium second messengers
Unlike hormones, not transported in the blood
Local mediators that act where synthesized or in adjacent cells
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a. the inflammatory response involving primarily the joints (rheumatoid arthritis) and skin (psoriasis);
b. the production of pain and fever;
c. the regulation of blood pressure (vaso-constrictors/dilators) and blood clotting (platelet function);
d. decreased gastric acid secretion (prostacyclins may be an ideal way to control the symptoms of peptic ulcer, but prostanoid synthesis inhibitors, like aspirin, increase acid secretion causing peptic ulcer);
e. the control of several reproductive functions such as the induction of labor and delivery - this has led to the use of PGF2 as a mid-trimester abortifacient drug or as a labor-inducing agent;
f. the regulation of the sleep/wake cycle;
g. hypersensitivity allergic reactions (a primary action of leukotrienes).
The Actions of Prostaglandins and Leukotrienes
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esterification
Membrane phospholipids
Dietary linoleic acid
Arachidonic acid
metabolism
Cell Activation Events: mechanical trauma, cytokines growth factors
Anti-inflammatory glucocorticoids
Prostaglandins and thromboxanes(Cyclic/ring product)
Phospholipase A2 (PLA2)
Leukotrienes(Linear product)
Arachidonic acid
Cyclooxygenase(COX)
Lipooxygenase(LOX)
Zyflo
Aspirin, Indomethacin, Ibuprofen NSAIDs
Figure 1. Liberation of arachidonic acid and its metabolism to prostaglandins/ thromboxanes or to leukotrienes
GC induce lipocortin that inhibits PLA2
Aspirin inhibits irreversiblyIndomethacin forms a salt bridge in the binding siteIbuprofen competes for substrate binding
Zyflo competes with AA for binding
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LEUKOTRIENE FACTS
leukotriene synthesis inhibited by Zyflo, a lipooxygenase inhibitor
leukotriene action blocked by accolate, a receptor antagonist
peptidoleukotrienes: leukotrienes with short peptides addedcomponents of slow reacting substances of anaphylaxis (SRS-A)anaphylaxis violent (potentially fatal) allergic reaction10,000 times more potent than histamineSRS-A released from lung following immunological stressSRS-A contract smooth muscle causing constriction of bronchiimplicated in hypersensitivity reaction – such as insect sting
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Arachidonic Acid (6)derived from membrane phospholipids
PGH2
central intermediate(Head of pathway)
Prostaglandinendoperoxidesynthase
Xaspirin
indomethacinibuprofen
GSSG
2GSH
PGG2
Cyclooxygenase
Hydroperoxidase
O2
Figure 3. Conversion of arachidonic acid to PGH2
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O
COOH
C
O
CH3
Ser
CH2 OH
Figure 4. Structure and mechanism of action of aspirin
OH
COOH
C
O
CH3CH2 O
AcetylatedCyclooxygenase
(inactive)
Ser
C
O
CH3
C
O
CH3
C
O
CH3C
O
CH3 C
O
CH3
Cyclooxygenase(active)
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COX-1 VS COX-2 DRUG ACTION
Aspirin:works on both isoformsCOX-1 effect reduces platelet aggregation (TXA2)COX-2 effect reduces inflammationSide effects due to COX-1 inhibition – stomach irritation
Specific COX-2 inhibitorsCelebrex/VioxxTarget inflammatory responseNo COX-1 inhibition to produce aspirin-induced side effects
Aspirin:works on both isoformsCOX-1 effect reduces platelet aggregation (TXA2)COX-2 effect reduces inflammationSide effects due to COX-1 inhibition – stomach irritation
Specific COX-2 inhibitorsCelebrex/VioxxTarget inflammatory responseNo COX-1 inhibition to produce aspirin-induced side effects
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Metabolism of Cholesterols
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Biosynthesis of Cholesterol Introduction
Functions of cholesterol. Important cell membrane component. Precursor for 3 biologically active compounds.
Bile. Steroid hormones. Vitamin D.
Disease implications. Cardiovascular disease.
Diet control and synthesis manipulation = < heart disorders.
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Biosynthesis of Cholesterol Introduction
Disease implications. Gall stones. Steroidogenic enzyme deficiency.
Source of cholesterol. Meat. Eggs. Dairy products. De novo liver synthesis.
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Cholesterol Synthesis
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Hydroxymethylglutaryl-coenzyme A (HMG-CoA) is the precursor for cholesterol synthesis.
HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA.
The enzymes for ketone body production are located in the mitochondrial matrix.
HMG-CoA destined for cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
CH2 C CH2 C
OH O
SCoA
CH3
C
O
O
hydroxymethylglutaryl-CoA
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HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase.
HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.
H3C C CH2 C
O O
SCoA
H3C C
O
SCoA
HSCoA
CH2 C CH2 C
OH O
SCoA
CH3
C
O
O
H2O acetoacetyl-CoA
hydroxymethylglutaryl-CoA
acetyl-CoA HMG-CoA Synthase
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The carboxyl of HMG that is in ester linkage to the CoA thiol is reduced to an aldehyde, and then to an alcohol.
NADPH serves as reductant in the 2-step reaction.
Mevaldehyde is thought to be an active site intermediate, following the first reduction and release of CoA.
+ HSCoA
H2CC
CH3HO
CH2
CO O
C SCoA
O
H2CC
CH3HO
CH2
CO O
H2C OH
2NADP+
2NADPH
HMG-CoA
mevalonate
HMG-CoAReductase
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HMG-CoA Reductase is an integral protein of endoplasmic reticulum membranes.
The catalytic domain of this enzyme remains active following cleavage from the transmembrane portion of the enzyme.
The HMG-CoA Reductase reaction, in which mevalonate is formed from HMG-CoA, is rate-limiting for cholesterol synthesis.
This enzyme is highly regulated and the target of pharmaceutical intervention.
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Mevalonate is phosphorylated by 2 sequential Pi transfers from
ATP, yielding the pyrophosphate derivative.
ATP-dependent decarboxylation, with dehydration, yields isopentenyl pyrophosphate.
H2CC
CH3HO
CH2
C O O
CH2 OH
H2C
C
CH2 CH2 O P O P O
O
O
O
O
CH3
H2CC
CH3HO
CH2
C O O
CH2 O P O P O
O
O
O
O
CO2
ATP
ADP + Pi
2 ATP
2 ADP
mevalonate
5-pyrophosphomevalonate
(2 steps)
isopentenyl pyrophosphate
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Isopentenyl pyrophosphate is the first of several compounds in the pathway that are referred to as isoprenoids, by reference to the compound isoprene.
isoprene
H2CC
CCH2
CH3
H
is o p e n te n y l p y ro p h o s p h a te
H 2 CC
CH 2
H 2C
C H 3
O P
O
O
O P O
O
O
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Isopentenyl Pyrophosphate Isomerase inter-converts isopentenyl pyrophosphate & dimethylallyl pyrophosphate.
Mechanism: protonation followed by deprotonation.
H2C
C
CH2 CH2 O P O P O
O
O
O
O
CH3
H3C
C
CH CH2 O P O P O
O
O
O
O
CH3
isopentenyl pyrophosphate
dimethylallyl pyrophosphate
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Prenyl Transferase catalyzes head-to-tail condensations:
Dimethylallyl pyrophosphate & isopentenyl pyrophosphate react to form geranyl pyrophosphate.
Condensation with another isopentenyl pyrophosphate yields farnesyl pyrophosphate.
Each condensation reaction is thought to involve a reactive carbocation formed as PPi is eliminated.
Condensation Reactions
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CH2 CH2 O P O P O
O
O
O
O
CH CH2 O P O P O
O
O
O
O
CH2C
CH3
CH3C
CH3
CH CH2CH3C
CH3
CH CH2 O P O P O
O
O
O
O
CCH2
CH3
PPi
CH2 CH2 O P O P O
O
O
O
O
CH2C
CH3
CH CH2CH3C
CH3
CH CH2CCH2
CH3
PPi
CH CH2 O P O P O
O
O
O
O
CCH2
CH3
dimethylallyl pyrophosphate
isopentenyl pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
farnesyl pyrophosphate
Each condensation involves a carbocation formed as PPi is eliminated.
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Squalene Synthase: Head-to-head condensation of 2 farnesyl pyrophosphate, with reduction by NADPH, yields squalene.
CH CH2CH3C
CH3
CH CH2CCH2
CH3
CH CH2 O P O P O
O
O
O
O
CCH2
CH3
2
O
NADP+
O2 H2O
HO
H+
NADPH
NADP+ + 2 PP i
NADPH
2 farnesyl pyrophosphate
squalene 2,3-oxidosqualene lanosterol
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Squaline epoxidase catalyzes conversion of squalene to 2,3-oxidosqualene.
This mixed function oxidation requires NADPH as reductant & O2 as oxidant. One O atom is incorporated into substrate (as the epoxide) & the other O is reduced to water.
O
NADP+
O2 H2O
HO
H+NADPH
squalene 2,3-oxidosqualene lanosterol
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Structural studies of a related bacterial enzyme have confirmed that the substrate binds at the active site in a conformation that permits cyclization with only modest changes in position as the reaction proceeds.
The product is the sterol lanosterol.
O HO
H+
2,3-oxidosqualene lanosterol
Squalene Oxidocyclase catalyzes a series of electron shifts, initiated by protonation of the epoxide, resulting in cyclization.
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Conversion of lanosterol to cholesterol involves 19 reactions, catalyzed by enzymes in ER membranes.
Additional modifications yield the various steroid hormones or vitamin D.
Many of the reactions involved in converting lanosterol to cholesterol and other steroids are catalyzed by members of the cytochrome P450 enzyme superfamily.
H O H O
lan o ste ro l ch o les te ro l
1 9 s tep s
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Regulation of cholesterol synthesis
HMG-CoA Reductase, the rate-limiting step on the pathway for synthesis of cholesterol, is a major control point.
Short-term regulation:
HMG-CoA Reductase is inhibited by phosphorylation, catalyzed by AMP-Dependent Protein Kinase (which also regulates fatty acid synthesis and catabolism).
This kinase is active when cellular AMP is high, corresponding to when ATP is low.
Thus, when cellular ATP is low, energy is not expended in synthesizing cholesterol.
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Long-term regulation is by varied formation and degradation of HMG-CoA Reductase and other enzymes of the pathway for synthesis of cholesterol.
Regulated proteolysis of HMG-CoA Reductase:
• Degradation of HMG-CoA Reductase is stimulated by cholesterol, oxidized derivatives of cholesterol, mevalonate, & farnesol (dephosphorylated farnesyl pyrophosphate).
• HMG-CoA Reductase includes a transmembrane sterol-sensing domain that has a role in activating degradation of the enzyme via the proteasome (proteasome to be discussed later).
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Long-term regulation is by varied formation and degradation of HMG-CoA Reductase and other enzymes of the pathway for synthesis of cholesterol.
Regulated proteolysis of HMG-CoA Reductase:
• Degradation of HMG-CoA Reductase is stimulated by cholesterol, oxidized derivatives of cholesterol, mevalonate, & farnesol (dephosphorylated farnesyl pyrophosphate).
• HMG-CoA Reductase includes a transmembrane sterol-sensing domain that has a role in activating degradation of the enzyme via the proteasome (proteasome to be discussed later).
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Lipid transport
• triacylglycerides, cholesterol, phospholipids
• dietary lipid transport –chylomicron
• endogenous lipid transport (VLDL, IDL, LDL, HDL)
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pancreaticlipases
intestinal lumentriacylglycerols FFA + monoacylglycedrols
bile acidscholesterol
micellesmicellesepithelial cellstriacylglycerols
absorbed by intestinal epithelial cells and reconverted to triacylglycerols
•Packaged into chylomicron•Released into lymphatic system and then via capillaries to blood stream
chylomicron
•acted upon by lipases on cell walls of capillaries in tissues
FFA • taken up by tissues
energy production
reconversion to TAGs in adipocytes for storage
hormone sensitive lipasesFFAreleased to circulatory system and combine with albumin fordelivery to tissues
Dietary uptake and distribution of fatty acids
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Why do we need lipoproteins? Triacylglycerides (TAGs) + cholesterol (Chol)
are nonpolar molecules → insoluble in H2O
TAG + Chol must be packaged within a polar shell in order to be transported through the blood to the various tissues
This is accomplished by combining nonpolar lipids w/ amphipathic lipids →(a polar water-soluble terminal group attached to an H2O -insoluble hydrocarbon chain)
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Lipoproteins & Apolipoproteins
Lipoproteins (LP) function: transport of cholesterol + esterified lipids in
blood structure:
1) polar shell ---single phospholipid (PL) layer: head groups directed outward
-Chol -apolipoproteins2) nonpolar lipid core
-hydrophobic TAG(triacylglycerol)-cholesteryl ester (CE)
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apolipoproteins• Provide structural stability to Lp
• Act as cofactors for enzymes involved in plasma lipid and Lp metabolism
• Serve as ligands for interaction w/Lp receptors that help determine disposition of individual particles
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There are many types of apolipoproteinsaApoprotein Lipoproteins Function(s)
Apo B-100 VLDL, IDL, LDL 1) Secretion of VLDL from liver 2) Structural protein of VLDL, IDL, and HDL 3) Ligand for LDL receptor (LDLR)
Apo B-48 Chylomicrons, remnants
Secretion of chylomicrons from intestine; lacks LDLR binding domain of Apo B-100
Apo E Chylomicrons, VLDL, IDL, HDL
Ligand for binding of IDL & remnants to LDLR and LRP
Apo A-I HDL, chylomicrons 1) Major structural protein of HDL2) Activator of LCAT
Apo A-II HDL, chylomicrons Unknown
Apo C-I Chylomicrons, VLDL, IDL, HDL
Modulator of hepatic uptake of VLDL and IDL (also involved in activation of LCAT)
Apo C-II Chylomicrons, VLDL, IDL, HDL
Activator of LPL
Apo C-III Chylomicrons, VLDL, IDL, HDL
Inhibitor of LPL activity
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Lipoprotein Structure
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Lipoproteins• hydrophobic core (TAGS, cholesterol esters)• hydrophilic surface (P-lipids, cholesterol, and
apolipoproteins)
• Functiontransport of lipids in blood
• Types of lipoproteins(classified according to density)
• very low density (VLDL)• intermediate density (IDL)• low density (LDL)• high density (HDL)Protein content increase, lipid decreases as density increases.
% TAGS
% Protein
Chylomicron VLDL IDL LDL HDL85%
2%
8%
33%
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nm
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Lipoproteins
• Chylomicron:
• 85% TAG, 4% chol., 8% protein•formed in intestinal epithelial cells• deliver exogenous TAGS to tissue• 80 -500nm• ApoCII activates lipases in capillary cell walls releasing FFA to tissue
• chylomicron remnants return to liver where they bind to ApoE receptor and are taken up
• 1/2 life in blood - 4-5 minutes
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• VLDL:
• 50% TAGs, 22% choles., 10% protein• 30 -100 nm • formed in liver• deliver endogenous lipids to other tissues(mainly muscle and fat cells)
• ApoCII activates lipases in capillary cell walls releasing FFA to tissue
• converted to IDLs and LDL as lipids are released
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• IDL: (31% TAGs, 29% choles., 18% protein) • formed from VLDLs as lipids removed• some IDLs return to liver• rest converted to LDLs by further removal of lipids
Lipoproteins
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• LDL: “bad” cholesterol• •10% TAGs, 45% choles., 25% protein• 25 - 30 nm• formed as lipids removed from VLDLs
and IDLs. • all apolipoproteins lost except ApoB100• bind to LDL receptor via ApoB100 and
taken up by endocytosis by hepatic and other tissues (50-75% taken up by liver).
• Primary mode of cholesterol delivery to tissues.• Synthesis of LDL receptor is inhibited by
high levels of intracellular cholesterol and stimulated by low levels of cholesterol.Therefore, cholesterol uptake is closely matched to intracellular cholesterol levels.
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• HDL: “good” cholesterol
• 8% TAGs, 30% choles., 33% protein• 7.5 - 10 nm• formed in liver• scavenge cholesterol from cell surfaces
and other lipoproteins and deliver it to liver.• Convert cholesterol to cholesterol ester• bind to “scavenger receptor” on liver cell
surface - cholesterol esters taken up and HDLs released and reenter circulation.
Lipoproteins
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Intestine Liver
Dietary lipids
chylomicron
Peripheral tissues
Dietary lipids
chylomicron
LDLs
TriacylglycerolsFFA
monoacylglycerols
Cholesterol
Cholesterol esters
Triacylglycerolscholesterol
Cholesterol esters
VLDLs
HDL
HDLs
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Intestine Liver
Dietary lipids
chylomicron
Peripheral tissues
Dietary lipids
chylomicron
TriacylglycerolsFFA
monoacylglycerols
Cholesterol
Cholesterol esters
Distribution of endogenous lipids The Exogenous Pathway
LPLs activated by ApoCII
Chylomicronremnantsacquire
ApoE, CIIand others
ApoE/LDLRmediated
uptake
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Liver
Peripheral tissues
LDLs
TriacylglycerolsFFA
monoacylglycerols
Cholesterol Ester
Cholesterol
Triacylglycerolscholesterol
Cholesterol esters
VLDLs
IDLs
Distribution of endogenous lipids The Endogenous Pathway
acquireApoE, CIIand others
LPLs activated by ApoCII
LDLR/ApoE
LDLR/ApoB100
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Distribution of endogenous lipids The HDL Pathways
Transport of excess cholesterol from peripheral tissues back to liver for excretion in bile
HDLs act as acceptors for excess chol, Apo, PL derived fromCM, VLDL and LDL
HDLs synthesized by both liver and intestine
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Liver
Peripheral tissues
LDLs
TriacylglycerolsFFA
monoacylglycerols
Cholesterol Ester
Cholesterol
Triacylglycerolscholesterol
Cholesterol esters
VLDLs
HDL
HDLs
IDLsCEs
TAGs
Distribution of endogenous lipids The HDL Pathways
scavenger receptoruptake of cholesterol
VLDLCholes.
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Abnormal Metabolism of Lipoprotein
Hyperlipoproteinemia Genetic diseases