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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.
脂質的運送
© 2014 John Wiley & Sons, Inc. All rights reserved.
Lipoproteins transport cholesterol and
other fats.
(缺脂)脂蛋白
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?
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.
Atherosclerosis 動脈粥狀硬化
何種脂蛋白在Atherosclerosis的起始扮演重要角色?
脂質的分解
© 2014 John Wiley & Sons, Inc. All rights reserved.
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.
• 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?
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
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
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?
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
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
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
The reactions of β oxidation
Step 2 Hydration 水合
The reactions of β oxidation
Step 3 2nd β-carbon oxidation (NAD+)
氧化
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?
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?
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
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
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
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
Breakdown of Propionyl-CoA
© 2014 John Wiley & Sons, Inc. All rights reserved.
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?
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.
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
The function of peroxisomes
1. Very-long-chain fatty acid shortening
system
2. Branched-chain fatty acid (not recognized
by mitochondrial enzymes)
脂肪的合成
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
17-2 Fatty Acid Synthesis
pantothenate (vitamin B5)
The citrate transport system
Fatty acid synthesis
in cytosol
Acetyl-CoA is generated
in mitochondria
(from pyruvate dehydrogenase)
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
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
Fatty acid synthesis begins with two
transacylation reactions.
Then, the two products are condensed…
© 2014 John Wiley & Sons, Inc. All rights reserved.
Condensation in
Fatty Acid Synthesis
© 2014 John Wiley & Sons, Inc. All rights reserved.
Fatty acid synthesis
Step 3-7 ElongationNADPH generates from
pentose phosphate pathway
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.
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
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.
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.
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).
Control of
Fatty Acid
Metabolism
Inhibition
Activation
© 2014 John Wiley & Sons, Inc. All rights
reserved.
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.
Ketogenesis
breath a characteristic
sweet smell
During periods of high ketogenic activity,
ketone bodies may be produced
faster than they are consumed.
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.
17-3 Synthesis of Other Lipids
• Other Lipids:
Triacylglycerols
Glycerophospholipids
Sphingolipids
Cholesterols
Triacylglycerols and phospholipids are
built from acyl-CoA groups
• Glycerol backbone from glycolytic intermediates
Synthesis of diacylglycerol and
triacylglycerol
Backbone +R1 +R2
+R3
Synthesis of phosphatidylethanolamine
and phosphatidylcholine
Synthesis of phosphatidylethanolamine
and phosphatidylcholine
Synthesis of phosphatidylserine
Synthesis of phosphatidylinositol
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
Cholesterol synthesis begins with
acetyl-CoA
• Mevalonate + 2 Pi – CO2
→ Isopentenyl pyrophosphate
Six isoprene units condense to form the
C30 compound squalene
Cholesterol can be used in several ways.
• Embedded into membranes
• Converted into esters for transport
© 2014 John Wiley & Sons, Inc. All rights reserved.
Cholesterol can be used in several ways.
• Cholesterol can be a precursor of:
– Hormones such as testosterone, estrogen
– Bile acids such as cholate
© 2014 John Wiley & Sons, Inc. All rights reserved.
Statins
• Statins have an HMG-like group that acts as
competitive inhibitor of HMG-CoA binding to the
enzyme
Cells can synthesize cholesterol
as well as take it up from
circulating low-density lipoproteins.
© 2014 John Wiley & Sons, Inc. All rights
reserved.
High-density lipoproteins
remove excess cholesterol from
cells.
© 2014 John Wiley & Sons, Inc. All rights
reserved.
Summary of
Lipid
Metabolism
© 2014 John Wiley & Sons, Inc. All rights
reserved.
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