Physiological Chemistry
Lipid Metabolism
Chapter 23
Digestion 23.1
• 98% of total dietary lipids is triacyglycerols
(fat and oils)
• Stomach:
– Physical changes mostly (formation of large
lipid droplets)
– Hydrolysis from proteins
– Gastric lipases (some hydrolysis)
Digestion
• Small Intestines
– Lipids stimulate secretion of cholecystokinin
(CCK)
• Contraction of gall bladder and release of bile
– Releases bile salts, cholesterol, and phospholipids to
emulsify triacylglcerols
– Allows pancreatic lipase to digest
triacylglcyerol (hydrolysis to fatty acids and
monoacylglycerols) and eventually form
“micelles”
‹#›
Hydrolysis of Triacylglycerols (Fat)
Products of Lipid Digestion
• Smaller components
– Free fatty acids (short, medium and long
chain)
– Monoacylglycerols
– Phospholipids and lysophospholipids
– Free cholesterol
– Fat soluble vitamins
– Bile acids
Absorption
• Passive diffusion of micelle into small
intestinal cells
• Micelles diffuse through the cell membrane
• About 100% of dietary fat and 50% of
dietary cholesterol is absorbed (about 80%
of bile acids reabsorbed)
‹#›
Metabolism of Absorbed Lipid
• Free fatty acids (FA) absorbed in small
intestinal cell:
– Short-chained FA go directly into portal blood
and bind to albumin
– Other FA are re-esterified to other lipids to reform triacylglycerols, phospholipids and
cholesterol esters
• Newly formed triacylglycerols, cholesterol
esters, free cholesterol and phospholipids
are carried on a apoprotein to form
chylomicrons
Chylomicrons
• Made by small intestinal cells
• Move from small intestines to lymphatic system
and then to general blood stream
• Triacylglycerol (fat) is removed from blood by
lipoprotein lipases in adipose tissue and skeletal
muscle and other lipids removed by liver
• Appear in blood within 2 hours, peak at about 5-6
hours and are completely cleared in about 10
hours post meal (dependent upon fat content of
meal)
– May take up to 16 hours
Digestion and Absorption
The events that must occur before triacylglycerols can
reach the bloodstream through the digestive process.
‹#›
Triacylglycerol (Fat) Storage
• Fat is stored in adipose tissue mostly, a little
in skeletal muscle
• Provides insulation and protection
• Stored energy reserves
• Fat droplet occupies most of cell
• As fat accumulates, cell enlarges and then
splits in to 2 cells
Adipocyte
Structural
characteristics of
the adipose cell.
Fat Storage
• Fat can be stored virtually limitlessly
• In short any of us could weigh 500 pounds!
• Obesity can result from either an increased
number of fat cells or an enlargement of
existing fat cells
‹#›
Fatty Acid Degradation
(Lipolysis) 23.2
• Stimulated by epinephrine (fasting or physical
activity)
• Causes cyclic AMP production in adipocyte
(via adenyl cyclase)
• Cyclic AMP activates hormone sensitive
lipases (HSL) in adipocyte
• HSL hydrolyzes free fatty acids (which bind
to albumin) and glycerol that are released into
blood
• Relatively slow (muscle energy)
Epinephrine Action
Glycerol Metabolism
• Cytosol of muscle cell:
• DHAP enters glycolysis to produce
glyceraldehyde-3-P
• Produces about 20 ATPs
‹#›
Fatty Acid Oxidation
• FA oxidized into Acetyl CoA (-Oxidation)
- mitochondria
- makes ATP
- uses NAD+ and FAD as coenzymes
Activation and Transport of FA
- on outer surface of mitochondria
- acyl CoA diffuses across outer membrane
b. Acyl CoA + carnitine  Acylcarnitine + CoA
- Mitochondrial intermembrane space
Activation and Transport of FA
c. Acylcarnitine gets through inner
membrane via protein carrier into the
mitochondrial matrix
d. Once in the mitochondrial matrix:
Acylcarnitine + CoA  Acyl-CoA +
carnitine (re-used)
e. Acyl-CoA  -Oxidation Pathway
‹#›
Carnitine Transport
-Oxidation
- A series of decarboxylation reactions
- Repeated removal of 2 C to form acetyl-CoA
from carboxylic acid end of FA
- The removal of each 2 C is referred to as one
complete cycle, however, many individual
reactions (steps) occur in one cycle
Steps
1. Acyl CoA(n) loses 2 H’s and FAD
2 ATP's
FADH2; make
2. Add water (H2O) to acyl CoA(n)
3. Acyl CoA(n) loses 2 H’s and NAD+
make 3 ATP's
NADH;
4. Acyl CoA(n) → acyl CoA(n-2 carbons) + Acetyl-CoA
‹#›
Steps
5. Acetyl-CoA goes into the Citric Acid
Cycle to produce 12 ATPs
6. Acyl CoA, now 2 carbons shorter, goes
back to step 1 and repeats the cycle until
the molecule is completely oxidized
(converted into acetyl CoA molecules)
Complete Oxidation and ATP
Production
• For C16 (Stearate)
• 7 cycles occur
– Forms 7 NADH and 7 FADH2 = 35 ATPs
– 8 Acetyl-CoAs produced = 96 ATPs (Citric Acid
Cycle)
– 2 ATPs are used to form acyl CoA (initially)
– Total Net = 129 ATPs from C16 Fatty Acid
Ketone Bodies 23.3
• Ketone body formation occurs in the
mitochondria of liver cells and is caused by
high rate of fat catabolism during low
glucose catabolism
• When glucose catabolism decreases,
pyruvate supply becomes depleted and leads
to an oxaloacetate deficiency
‹#›
Ketone Bodies
• This slows down the citric acid cycle
• Increase fat catabolism produces excess
acetyl-CoA from oxidation, which cannot
enter citric acid cycle
• This leads to an accumulation of acetylCoAs and turns on ketogenesis
• Ketosis is the presence of ketone bodies in
the blood and urine
– Eventually this can lead to ketoacidosis
Ketogenesis Pathway
• Step 1: 3 acetyl-CoA  HMG-CoA (6C)
+ CoA
• Step 2: HMG-CoA  Acetoacetate
(ketone body) + Acetyl-CoA
Ketogenesis Pathway
• Step 3a: Acetoacetate  acetone (ketone
body) + CO2 spontaneously
- acetone is then breathed out from lungs,
released through skin pores, urine
• Step 3b: Acetoacetate + NADH + H+ 
β-hydroxybutyrate (ketone body) + NAD+
‹#›
Ketogenesis Pathway
• Acetone gives “sweet smell” to breath/urine
and ketone bodies decrease plasma pH
• This decreases plasma bicarbonate and
leads to ketoacidosis (metabolic acidosis)
• Also, increased solute in plasma causes a
fluid shift from ICF to ECF
Ketogenesis Pathway
• This can lead to extracellular edema (and
finally to intracellular dehydration)
• Occurs when glucose metabolism is not
occurring or taking place too slowly
• Common in: type I diabetes, low
carbohydrate diets, fasting, starvation
Fatty Acid Synthesis (Lipogenesis)
23.4
• Synthesis of fatty acids from excess acetylCoA
– Occurs in the cytosol of mostly liver and
adipose tissue cells
– Fatty Acid Synthase Complex
– Compounds are attached to acyl carrier protein
(ACP)
– Needs NADPH to act as a reducing agent
– Due to excess calorie (energy) intake from
carbohydrates, protein, and alcohol followed by
resting
‹#›
Lipogenesis
• The major steps are:
– Formation of malonyl-CoA
– ACP complex formation
– Chain elongation to palmitic acid
• Humans can convert glucose to fatty acids via
acetyl-CoA (lipogenesis) but cannot do the
reverse
Lipogenesis
• Humans can break fatty acids down to acetylCoA, but we cannot convert it into pyruvate or
oxaloacetate, which could be used for
gluconeogenesis
• Thus to lose extra fat, humans must burn fat as
an energy source (being physically active
before and/or after meals)
Citrate-Malate Shuttle
• Since acetyl-CoA is produced in the
mitochondria and lipogenesis occurs in the
cytosol the first step is to get excess acetylCoAs out of the mitochondria to the cytosol
• Acetyl CoA + oxaloacetate → citrate
(transported out through inner
mitochondrial membrane by the citratemalate shuttle [protein])
‹#›
Citrate-Malate Shuttle
• Once in the cytosol:
• citrate → acetyl-CoA + oxaloacetate
– with help from ATP
• acetyl-CoA goes into lipogenesis
Formation of Malonyl-CoA
• Acetyl-CoA  Malonyl-CoA by
carboxylation reaction (C2 to C3)
ACP Complex
• Acetyl-CoA and Malonyl-CoA are then
attached to ACP
• Become acetyl-ACP and malonyl-ACP
‹#›
Chain Elongation
• Acetyl-ACP + Malonyl-ACP 
Acetoacetyl-ACP + ACP + CO2
– (2 carbons + 3 carbons  4 carbons +
1 carbon, leaving as CO2)
• Acetoacetyl-ACP is converted into ButyrylACP (still 4 carbons) by rearrangement
reactions (reduction)
Rearrangement
Reactions
Cycles of fatty acid
biosynthesis
pathways
Chain Elongation
• After the rearrangement reactions, another
malonyl-CoA is formed and attached to the
butyryl-ACP (repeat previous steps) to form
a 6 carbon molecule, which is also reduced
• Process repeats until palmityl-ACP (C16) is
formed and then palmitic acid detaches
from ACP Complex
• Other enzymes are needed for further
elongation, but still result in fatty acids with
an even carbon number
‹#›
Cholesterol Synthesis
• Occurs primarily in the liver and small
intestines
• Made from 15 acetyl-CoA molecules,
(contains 27 carbons)
• Approximately 1.5 – 2.0 g/day is
synthesized in the different tissues
• Approximately 0.30 g/day is consumed in
the diet
Cholesterol Synthesis
• Essential for structure and function of cell
membranes
• Precursor to steroid hormones (progestins,
estrogens, androgens, glucocorticoids, and
mineralcorticoids), vitamin D, and bile
acids
Cholesterol Synthesis
• 5 stages:
– Synthesis of Mevolonate from acetyl-CoAs
• HMG CoA reductase (regulating enzyme)
– Synthesis of Isopentenyl pyrophosphate
(isoprenoids)
– Synthesis of Squalene from several isoprenoids
• Acyclic (non ring structure)
– Synthesis of Lanosterol (1st sterol)
• Multi-ring structure
– Synthesis of Cholesterol
‹#›
Biosynthetic Pathway for Cholesterol
Synthesis
Cholesterol
• HMG CoA Reductase inhibitors can
sometimes lower serum cholesterol by
inhibiting cholesterol synthesis within the
cell thus cell must get it’s source of
cholesterol from the blood
• Called “statins”
– i.e. atorvastatin (Lipitor), lovastatin (Mevacor),
simvastatin (Zocor)
Relationship between Lipids and
Carbohydrates 23.5
• Acetyl-CoA is primary link
• Both fat and carbohydrates produce acetyl
CoA for citric acid cycle for energy during
fasting and physical activity
• Excess acetyl CoAs from carbohydrate
consumption can produce fat and eventually
lead to increase fat storage
‹#›
Relationship between Lipids and
Carbohydrates
• Ketosis occurs when there is decreased
glucose catabolism and adequate fatty acid
catabolism
• Fatty acid and cholesterol synthesis occurs
when the body is in an acetyl CoA-rich state
but doesn’t need energy
‹#›