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Lecture Notes for
Chapter 17Lipid Metabolism
Essential BiochemistryThird Edition
Charlotte W. Pratt | Kathleen Cornely
Copyright © 2014 John Wiley & Sons, Inc. All rights reserved.
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脂質的運送
© 2014 John Wiley & Sons, Inc. All rights reserved.
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Lipoproteins transport cholesterol and
other fats.
(缺脂)脂蛋白
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Lipoprotein functions
乳糜微粒
• Chylomicrons (CM)
• transport fats from intestines to tissues.
• Very-low-density lipoproteins (VLDL)
• transport triacylglycerols from the liver
to other tissues.
• Low-density lipoproteins (LDL)
• carry cholesterol to the tissues.• LDL levels should be relatively low.
• “Bad cholesterol.”
• High-density lipoproteins (HDL)
• export cholesterol from the tissues to
the liver.• HDL levels should be relatively high.
• “Good cholesterol.”
何者將脂質由週邊組織運往肝臟?
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Approximately half of all deaths in
the US are linked to atherosclerosis.
• Atherosclerosis
– A slow progressive
disease
– Characterized by
hardening of the
arteries due to
lipid accumulation
in blood vessel
walls
© 2014 John Wiley & Sons, Inc. All rights reserved.
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Atherosclerosis 動脈粥狀硬化
何種脂蛋白在Atherosclerosis的起始扮演重要角色?
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脂質的分解
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Lipid Metabolism In
Context
• Triacylglycerols contain fatty
acids attached to a glycerol
backbone.
• Fatty acids are broken down
into 2C and 3C intermediates
that feed into the citric acid
cycle.
© 2014 John Wiley & Sons, Inc. All rights reserved.
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• Primary source of fatty acid fuel:
dietary triacylglycerols
17-1 Fatty Acid Oxidation
Many free fatty acid are deployed to the liver and muscle cells, especially
heart muscle何種組織主要以Free fatty acid作為能量來源?
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Fatty acids are activated before they
are degraded
Acyl-CoA synthetase (ACS)
Fatty acid要分解要先”活化”
“活化” = 預先轉移ATP能量至” CoA”結構
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Acyl-CoA synthetases
• 脂肪酸依長鏈數目有不同的類別
– Short (C2-C3)
– Medium (C4-C12)
– Long (≧C12)
– Very long (≧C22)
• 脂肪酸透過滲透作用進細胞,Acyl-CoA synthetase與membrane transport protein協同活化脂肪酸
• 一旦脂肪酸被活化,則無法再滲透出membrane (Acyl-CoA)
• 要繼續分解,則要先將Acyl-CoA運進粒線體
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The carnitine shuttle system:
Transport acyl groups into
mitochondria
Fatty acid activated
in cytosol
β-Oxidation
in Mitochondria
何種shuttle system將Acyl group運進粒線體?
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Each round of β oxidation has four
reactions
• β oxidation:
Acetyl-CoA進入粒線體後,以2個碳為單位減少的過程稱之
• 因為發生在β position (自Carbonyl carbon起算),故稱為β-oxidation
Carbonyl carbonC3
C2
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Each round of β oxidation has four
reactions
• 每回合4個催化步驟
• 產生一個Acetyl-CoA (2C)
• 原先的長鏈減少2C直到底
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The reactions of β oxidation
Step 1 1st β-carbon oxidation (FAD) 氧化
Oxidative
Phosphorylation
Acyl-CoA dehydrogenases:
不同長度的Acyl-CoA由不同的ACDH
作用
中鏈醯輔酶A去氫酶缺乏症Medium-chain acyl-CoA
dehydrogenase (MCAD) deficiency
脂肪酸氧化障礙,會導致能量不足及代謝中毒產生腦病變、心肌病變、及肌肉病變等症狀。
氧化 = 脫氫,產生FADH2
→QH2
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The reactions of β oxidation
Step 2 Hydration 水合
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The reactions of β oxidation
Step 3 2nd β-carbon oxidation (NAD+)
氧化
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The reactions of β oxidation
Step 4 Thiolysis 硫解
每回合β-oxidation後產生何者?
β-Oxidation中,何者非反應產物?
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β Oxidation results in ATP
production.
© 2014 John Wiley & Sons, Inc. All rights reserved.
每回合β-oxidation共產生多少 ATP?
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Degradation of unsaturated fatty acids
requires isomerization and reduction
當脂肪酸為不飽和脂肪酸,需要額外的步驟加以分解Isomerization and Reduction
由於長鏈脂肪酸以2碳遞減,故不飽和鍵只會有兩種情況:位於奇數 Cis 3,4
位於偶數 Cis 4,5
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Enoyl-CoA isomerase converts a cis 3,4
double bond to a trans 2,3 double bond so
that β oxidation can continue.
© 2014 John Wiley & Sons, Inc. All rights reserved.
位於奇數:Cis 3,4轉為Trans 2,3,接續第二步水合
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When linoleate is
degraded,
another double
bond blocks β
oxidation.
© 2014 John Wiley & Sons, Inc. All rights reserved.
位於偶數:第一步氧化後,與Cis 4,5形成共振以NADPH還原,形成Cis 3,4
再將Cis 3,4轉化為Trans 2,3,接續第二步水合
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Oxidation of odd-chain fatty acids yields
propionyl-CoA
• 大多數Fatty acid為偶數,最後一個亦為Acetyl-CoA
• 有些植物或細菌產生奇數長鏈Fatty acid,最後一個將為3
個碳的Propionyl-CoA
• 解法:消費ATP加一個碳,使其形成Succinyl CoA,進入TCA循環
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Breakdown of Propionyl-CoA
© 2014 John Wiley & Sons, Inc. All rights reserved.
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Methylmalonyl-CoA
mutase uses an unusual
cofactor.
© 2014 John Wiley & Sons, Inc. All rights reserved.
• Cofactor comes from the vitamin cobalamin.
何種維生素與3碳脂質小分子代謝有關?
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Some fatty acid oxidation occurs in
peroxisomes
• The majority of fatty acid oxidation occurs in
mitochondria.
• A small percentage is carried out in organelles known
as peroxisomes.
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Some fatty acid oxidation occurs in
peroxisomes
• Different First step Acyl-CoA dehydrogenase
in mitochondria
High affinity for
Very-long chain FA
→ chain-shortening
system
By peroxisomal enzyme catalase
2 H2O2 2 H2O + O2
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The function of peroxisomes
1. Very-long-chain fatty acid shortening
system
2. Branched-chain fatty acid (not recognized
by mitochondrial enzymes)
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脂肪的合成
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17-2 Fatty Acid Synthesis
• As glycolysis and gluconeogenesis, the pathways for
fatty acid synthesis and degradation must differ for
thermodynamic reasons.
β Oxidation Synthesis
Location Mitochondrial matrix Cytosol
Cofactors Coenzyme A Acyl-carrier protein
Energy
Transfer
Generate QH2 and
NADHConsume NADPH
ATP
requirements
2ATP once for acyl
group activation
1 ATP consumed for
each acetyl addition
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17-2 Fatty Acid Synthesis
pantothenate (vitamin B5)
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The citrate transport system
Fatty acid synthesis
in cytosol
Acetyl-CoA is generated
in mitochondria
(from pyruvate dehydrogenase)
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The first step of fatty acid synthesis
Carboxylation of acetyl-CoA
A. CO2 activation
B. Transfers the carboxylate group to acetyl-
CoA
Malonyl-CoA
(C3 intermediate)
the donor of the
two-carbon acetyl units
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Fatty acid synthase catalyzes seven
reactions
Fatty acid synthase:
•ACP: acyl-carrier proteinpantothenate arm swings between the
active sites
•6 active siteMAT: transacylase
TE: Thioesterase
KS: 3-ketoacyl-ACP syhthase
KR: 3-ketoacyl-ACP reductase
DH: 3-hydroxyacyl-ACP dehydrase
ER: enoyl-ACP reductase
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Fatty acid synthesis begins with two
transacylation reactions.
Then, the two products are condensed…
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Condensation in
Fatty Acid Synthesis
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Fatty acid synthesis
Step 3-7 ElongationNADPH generates from
pentose phosphate pathway
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Fatty acid synthesis
Step 8-9 Ending
• Fatty acid synthesis
cycles until a 16-C chain
is formed.
• A thioesterase releases
the acyl-carrier protein.
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ATP consumption in Fatty acid
synthesis
• Example: Palmitate (16C)
Derived from Acetyl-CoA (2C)
7 malonyl-CoA required (7ATP)
14 NADPH required (14 × 2.5 = 35ATP)
the total cost = 42ATP
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Advantages of multifunctional enzyme
• Allows the enzymes to be synthesized and controlled in
a coordinated fashion.
• The product of one reaction can quickly diffuse to the
next active site.
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Other enzymes elongate and desaturate
newly synthesized fatty acids
• In mammals, fatty acid synthase produces mostly the 16-
carbon saturated fatty acid palmitate.
• Some sphingolipids contain C22 and C24 fatty acyl
groups.
• These and other long-chain fatty acids are generated by
enzymes known as elongases.
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Other enzymes elongate and desaturate
newly synthesized fatty acids
• Desaturases:
introduce double bonds
into saturated fatty acids.
• Mammals cannot
introduce double bonds at
positions beyond C9 and
therefore cannot
synthesize fatty acids
such as linoleate and
linolenate (essential fatty
acid).
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Control of
Fatty Acid
Metabolism
Inhibition
Activation
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reserved.
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Acetyl-CoA can be converted to ketone
bodies
• Prolonged fast
→ glucose is unavailable from the diet
→ liver glycogen has been depleted
• Tissues depend on fatty acids released from stored
triacylglycerols.
• However, the brain does not burn fatty acids because
they pass poorly through the blood–brain barrier.
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Ketogenesis
breath a characteristic
sweet smell
During periods of high ketogenic activity,
ketone bodies may be produced
faster than they are consumed.
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Liver itself cannot catabolize ketone bodies
because it lacks one of the required enzymes,
3-ketoacyl-CoA transferase.
Catabolism of Ketone bodies
Ketone bodies produced by the liver are
used by other tissues as metabolic fuels
after being converted back to acetyl-CoA.
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17-3 Synthesis of Other Lipids
• Other Lipids:
Triacylglycerols
Glycerophospholipids
Sphingolipids
Cholesterols
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Triacylglycerols and phospholipids are
built from acyl-CoA groups
• Glycerol backbone from glycolytic intermediates
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Synthesis of diacylglycerol and
triacylglycerol
Backbone +R1 +R2
+R3
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Synthesis of phosphatidylethanolamine
and phosphatidylcholine
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Synthesis of phosphatidylethanolamine
and phosphatidylcholine
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Synthesis of phosphatidylserine
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Synthesis of phosphatidylinositol
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Cholesterol synthesis begins with
acetyl-CoA
• The first steps of
cholesterol synthesis
resemble those of
ketogenesis.
Ketogenesis
→ in mitochondria (liver)
→ Acetoacetate
Cholesterol
→ in cytosol
→ MevalonateRate-determining step
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Cholesterol synthesis begins with
acetyl-CoA
• Mevalonate + 2 Pi – CO2
→ Isopentenyl pyrophosphate
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Six isoprene units condense to form the
C30 compound squalene
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Cholesterol can be used in several ways.
• Embedded into membranes
• Converted into esters for transport
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Cholesterol can be used in several ways.
• Cholesterol can be a precursor of:
– Hormones such as testosterone, estrogen
– Bile acids such as cholate
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Statins
• Statins have an HMG-like group that acts as
competitive inhibitor of HMG-CoA binding to the
enzyme
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Cells can synthesize cholesterol
as well as take it up from
circulating low-density lipoproteins.
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reserved.
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High-density lipoproteins
remove excess cholesterol from
cells.
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reserved.
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Summary of
Lipid
Metabolism
© 2014 John Wiley & Sons, Inc. All rights
reserved.