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Lipid MetabolismBy Dr. Gamil Abdalla
1. Course outlines
1-Lipid digestion and absorption and their errors
2. Fate of absorbed lipids 3. Lipolysis and Lipogenesis 4. Fatty acid oxidation and synthesis 5. Ketogenesis and ketolysis 6. Cholesterol and Lipiprotein metabolis 7. Fatty liver
– Lipid familyTriglycerides (fats & oils)
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– Phospholipids – Sterols (cholesterol) – cholesterol esters are digested by esterase to fatty
acids and cholesterol which absorbed as such
• • • As storage and transport form of metabolic fuel
• To keep the body temperature • Source for essential FA and oil soluble vitamins • To protect important organs
• Challenges
– Lipids are not water soluble – Triglycerides too large to be absorbed
• Digestive solution – Triglycerides mix with bile and pancreatic secretions
• Emulsification and digestion
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• Minor digestion of triacylglycerols in
1. Mouth by lingual lipase 2. Stomach by gastric lipase (in infants only). • Major digestion of all lipids in the lumen of the duodenum/
jejunum by Pancreatic lipases
•
Produced in liver, stored in gallbladder
•Alkaline solution composed of:
–Bile salts
–Cholesterol
–Lecithin
–Bilirubin
•Responsible for fat emulsification
----------------------------------------------------
Mixed micelle formed by bile salts,
triacylglycerols and pancreatic lipase.
• Bile salts emulsify lipids
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• Pancreatic lipase acts on triglycerides – Triglycerides
2 monoglyceride + 2 fatty acids • Pancreatic colipase
– Activated by trypsin – Interacts with triglyceride and pancreatic lipase
• Improves activity of pancreatic lipase
• Secreted from pancreas as procolipase
– Activated (cleaved) by trypsin
• Anchors lipase to the micel – One colipase to one lipase(i.e., 1:1 ratio)
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•Produces small lipid spheres
– Greater surface area • Lipases attack TG at 1 and 3 positions
1 2
3 4
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• Pancreatic insufficiency (chronic pancreatitis and
cystic fibrosis)
• Acidity of duodenal content (zollinger-Ellison syndrome)
• Deficiency of bile salts (ileal resection) • Bacterial over growth
• Decrease intestinal cells for absorption
• Failure of synthesis of apoproteins (abetalipoproteinemia)
1. Steatorhoea stool fat > 5 gm per day 2. Chyluria (milky urine)
Abnormal connections between lymphatics and urinary system.
1. Storage
2. Energy production 3. Gluconeogenesis
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4. Synthesis of
• Cellular structures • Biological active compounds eg. Prostaglandins
• Mainly as triacylglycerols (triglycerides) in adipose cells
• Constitute 84% of stored energy
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A- Definition: - Lipolysis is the hydrolysis of triacylglycerols in adipose tissue
into glycerol and fatty acids. Triglycerides Glycerol + 3 free fatty acids
B- Steps: - Lipolysis is carried out by a number of lipase enzymes, which
are present in adipose tissue. These are: 1. Hormone sensitive triacylglycerol lipase.
2. Diacylglycerol lipase. 3. Monoacylglycerol lipase.
I- Lipolysis
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Place: liver, kidney, intestine
•NoteIn muscle cells and adipocytes, the activity of glycerol kinase
is low, so these tissues cannot use glycerol as fuel.
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• TG lipase is the rate-limiting enzyme in the TG
degradation in adipose tissue. It is also named HSL becauseit is regulated by some hormones.
Effect of hormones on lipolysis
• Lipolytic Hormones:
epinephrine norepinephrine adrenocorticotropic hormone (ACTH)
• Hormone sensitive lipase (HSL)
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thyroid stimulating hormone (TSH)
Glucagon etc. • Antilipolytic Hormones: insulin
• - In conditions where the need for energy is increased e.g.:
• 1- Starvation.
• 2- Diabetes mellitus. • 3- Low carbohydrate diet.
•Beta oxidation (major catabolic pathway and never occurs in the
brain)
• Alpha oxidation
• Omega oxidation
• Cleavage of fatty acids to acetate in tissues
• Occurs in the mitochondria of liver, kidney and heart
• Never occur in the brain • Fatty acid catabolism can be subdivided into 3 stages.
•Stage 1 Activation of FasAcyl-CoA Synthetase (Thiokinase), which locates in the
cytoplasm, catalyzes the activation of long chain fatty acids.
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1. Irreversible
2. Consume 2 ~P 3. Site: cytosol
• Carrier: carnitine
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• Carnitine carries long-chain activated fatty acids into
the mitochondrial matrix
t into Mitochondrial Matrix2.Transpor
Stage 3: β-oxidation of FAs β-oxidation means β-C reaction.
Four steps in one round
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step 1: Dehydrogenate step 2: Hydration step 3: Dehydrogenate step 4: Thiolytic cleavage
Step 1. Dehydrogenate
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one cycle of the β-oxidation:
fatty acyl-CoA + FAD + NAD+
+ HS-CoA →fatty acyl-CoA (2 C
less) + FADH2 + NADH + H+
+ acetyl-CoA
The β-oxidation pathway is cyclic
Summary
The product of the
β-oxidation is in theform of FADH
2, NADH,
acetyl CoA, only after Krebs cycle andoxidative
phosphorylation, canATP be produced.
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-Oxidation of M ristic C14
-Oxidation of Myristic (C14) Acid
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Cycles of -Oxidation
The length of a fatty acid
• Determines the number of oxidations and the
total number of acetyl CoA groups
Carbons in Acetyl CoA -Oxidation Cycles
Fatty Acid (C/2) (C/2 –1)
12 6 5
14 7 6
16 8 7
18 9 8
ATP production for Myristic(14 carbons):
Activation of myristic acid -2 ATP
7 Acetyl CoA
7 acetyl CoA x 12 ATP/acetyl CoA 84 ATP
6 Oxidation cycles
6 NADH x 3ATP/NADH 18 ATP
6 FADH2
x 2ATP/FADH2 12 ATP
Total 102 ATP
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Oxidation of Special Cases
monounsaturated fatt acids
Odd Carbon Fatty Acids(13C)
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• This types of oxidation occurs in α position and
characterized by: 1- It is mechanism mainly for branched chain fatty acid,
which is methylated at β position. 2- It is specific for oxidation of phytanic acid. 3- It is minor pathway for fatty acid oxidation. 4- It occurs mainly in brain and nervous tissues.
PALMITIC ACID (16 C)
STEARIC ACID (18 C)
II- α-Oxidation:
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• In α-oxidation, there is one carbon atom removed at a
time from α position. • It dose not require CoASH and dose not generate high
energy phosphate.
Refsum’s disease:
This is inherited deficiency of enzymes responsible for α-
oxidation of phytanic acid. This leads to accumulation of phytanic acid in serum and nervous tissue and produce
nervous damage e.g. deafness and blindness.
1. It is oxidation of terminal CH3 group of
fatty acid.
2-It produces dicarboxylic fatty acids.
By β-oxidation, they are converted to
adipic acid (6 carbons) and suberic acid
(8 carbons).
2-It is a minor pathway forfatty acid oxidation and
used for oxidation of long chain fatty acids.
ω-Oxidation
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Formation and Utilization
• Ketone bodies are:
• water-soluble fuels • Normally exported by the liver
• overproduced during fasting or in untreated diabetes
mellitus.
Ketone Bodies
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The formation of ketone bodies (Ketogenesis)
Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase
Utilization of ketone bodies (ketolysis)
Occurs at extrahepatic tissues
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Occurs at extrahepatic tissues due to
Lack of succinyl-CoA transsulfurase and
Acetoacetate thiokinase in the liver.
• Ketone bodies are water soluble, they are convenient to
transport in blood, and readily taken up by non-hepatic
tissues
☻ In the early stages of fasting, the use of ketone bodies
by heart, skeletal muscle conserves glucose for support of central nervous system.
☻ With more prolonged starvation, brain can take up
more ketone bodies to spare glucose consumption
• High concentration of ketone bodies can induce ketonemia
and ketonuria, and even ketosis and acidosis
When carbohydrate catabolism is blocked by a disease of
diabetes mellitus or defect of sugar source, the blood
concentration of ketone bodies may increase,the patient may
suffer from ketosis and acidosis
The significance of ketone bodies
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Ketosis consists of ketonemia, ketonuria
and smell of acetone in breath
• Severe diabetes mellitus
• Starvation • Hyperemesis (vomiting) in early pregnancy
Causes for ketosis
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CH3COCH2CO2H pKa = 3.6
Acetoacetic Acid
CH3CHCH2CO2H pKa = 4.7b-Hydroxybutyric acid
Concentration of acetoacetic acid can result in metabolic
acidosis affinity of Hb for O2 coma death
Definition:- A
- Lipogenesis is the synthesis of triacylglycerol from fatty acids(acyl CoA) and glycerol (glycerol-3-phosphate). B- Steps: 1- Activation of fatty acids into acyl CoA:
Metabolic Acidosis in
Untreated Diabetes Mellitus
Lipogenesis
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2- Synthesis of glycerol-3- phosphate:
3-Formation of TAG
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After meal, lipogenesis is stimulated: - Insulin is secreted which stimulates glycolysis. Glycolysis supplies
dihydroxyacetone phosphate that converted into glycerol-3-phosphate in
adipose tissue, so lipogenesis is stimulated. During fasting lipogenesis is inhibited: - Anti-insulin hormones are secreted. These inhibit lipogenesis and
stimulate lipolysis
......
Regulation of lipogenesis