LIPIDS METABOLISM 1 Dr.

Amal Ghanim, PhD

Main points
• Lipid Metabolism
• Digestion of lipids
• Absorption of lipids
• Fatty acids synthesis
• Lipogenesis
Lipid Metabolism
• Adult human eats about 100-150 gm/day lipids

• The main lipids in our diet are TG (99%) and also contains
some phospholipids, cholesterol and fat soluble vitamins
Digestion of lipids
Triglycerides are digested by a group of enzymes:
 Lingual, Gastric, Pancreatic, and intestinal lipase

1- lingual and gastric lipase:

• Digestion of TG by lingual and gastric lipase is minimum

• Because food remains for short time in the mouth, lingual lipase effect on TG is minimal

• Gastric lipase needs optimum pH of 4 to 6 to be active. Thus cannot act in adults stomach
(pH 1-2). However, it play a particularly important role in lipid digestion in neonates
(stomach pH 5) for whom milk fat is the primary source of calories
Digestion of lipids
2- Pancreatic lipase:
• Its secretion is stimulated by pancreozymin hormone (secreted by the
duodenum) and vagus nerve stimulation.
• Activated by pancreatic colipase, bile salts and Ca ion
• It is specific for the primary ester links (positions 1 and 3 in triacylglycerols)
resulting in 2-monoacylglycerols and free fatty acids as the major end
products of luminal triacylglycerol digestion
Digestion of lipids
2- Pancreatic lipase:
• The resulted 2-monoacylglycerols will undergo:
 72% are absorbed as it is
28% are converted to 1- monoacylglycerol by isomerase. Thus, lipase can
hydrolyze it into glycerol and free fatty acids
• Bile salts presence is important for activation of pancreatic lipase and also
for emulsification of lipid ( breakdown of large fat globules into small ones)
to increase the surface area of lipid exposed to lipase enzymes.

3- Intestinal lipase :
Act also on 1- monoacylglycerol ,
hydrolyze it into free fatty acids
and glycerol
Digestion of cholesterol
• Cholesterol itself undergoes no digestion and absorbed as it is
• Cholesterol ester is digested by pancreatic cholesterol esterase
• So, the end products of lipids digestion are:
 Monoacylglycerols, fatty acids (short and long chain fatty acids
Glycerol
Phospholipids
Cholesterol
 Absorption of lipids
Intestinal cells Intestinal lumen

Glycerol Glycerol
Portal
circulation
Short Chain FA
Short Chain FA

Bile salts
+
Bile salts Monoacylglycerols

Micelles
+
Long chain FA
+
Thoracic Cholesterol
duct +
Phospholipids

Chylomicron
Absorption of lipids
• Short chain fatty acids (less than 12 carbon) and glycerol, phospholipids, and cholestrerol

are absorbed directly

• The fat-soluble vitamins, A, D, E, and K are dissolved and absorbed in the lipid micelles.

Absorption of the fat-soluble vitamins is impaired on a very low fat diet.

• Other lipid are water insoluble. They combine with the aid of bile salt to form micelles which

can enter from intestinal lumen to intestinal cells mucosa

Absorption of lipids
• Bile salts are reabsorbed to the liver again

• Long chain fatty acids are activated in intestinal cells and combine with mono &
diacylglycerol to form triacylglycerol again

• TG+ Phospholipids+ Cholesterol are bound to protein (apolipoprotein B48) to

form chylomicron which can enter the circulation via lymphatic tissue in thoracic
duct

• In blood: Chylomicron are bound with other 2 protein (Apolipoprotein E&C)

Fate of absorbed lipids
• After fatty meals, plasma shows a milky appearance due to excess chylomicron level after
absorption in blood

• This excess chylomicron is metabolized by lipoprotein lipase that hydrolyze triglyceride in

chylomicron into glycerol and free fatty acids

• Glycerol and fatty acids are taken by different tissue for the following fate:

 Formation of depot fat (adipose tissue): Lipogenesis

 Synthesis of cholesterol and phospholipid

 Oxidation for production of energy: Beta oxidation of fatty acids

 Glycerol form glucose formation by gluconeogenesis

Fatty Acid Synthesis- Lipogenesis
 Fatty acid synthesis occurs mainly in cytosol in fat tissue (adipose tissue), the
liver and mammary gland during lactation.
 Precursors are acetyl-CoA and malonyl-CoA
• Acetyl-CoA conversion to fatty acids is the major pathway for utilizing excess
dietary carbohydrates.
• In case of high blood glucose level, fed state,
the body tend to form fatty acid as a store for
excess glucose
• Humans can store only a few hundred grams of
glycogen in liver and muscle, barely enough to
supply the body’s energy needs for 12 hours.
• In contrast, the total amount of stored
triacylglycerol in a 70-kg man of average build
is about 15 kg, enough to support basal energy
needs for as long as 12 weeks

Malonyl CoA
Steps of fatty acid synthesis
1- Acetyl-CoA transported into cytosol
• Acetyl-CoA is generated in the
mitochondria primarily from
- The pyruvate dehydrogenase (PDH)
reaction Citrate
Citrate
lyase
synthase

Malic
enzyme

• Most of acetyl-CoA is transported into

Anaerobic reaction
cytosol in the form of citrate (citrate of krebs Used in fatty
acid synthesis
shuttle)
Steps of fatty acid synthesis
2- Activation of acetyl CoA to malonyl CoA
• Malonyl CoA is synthesized from Acetyl CoA using CO2 and ATP by acetyl
CoA carboxylase (using Biotin as co enzyme)

• 7 from the 8 transported acetyl coA converted to malonyl

• Acetyl CoA carboxylase (ACC) enzyme occurred in dimeric inactive (P form)

form to be activated it should be polymerized (Dephosphorylated form)
• ACC is highly regulated:
1- Allosteric regulation:
 Citrate activate ACC +ve
 Long chain fatty acid –CoA inhibit ACC –ve
2- Hormonal regulation:
 Insulin +ve
 Glucagon, Epinephrine and nor epinephrine -ve
Long chain fatty acid –CoA
Glucagon, Epinephrine and nor epinephrine
+

+
Citrate
Insulin
Steps of fatty acid synthesis
3- Fatty acid synthesis
Fatty acid synthesis is carried out by a group of enzymes collectively called
fatty acid synthase complex

• Fatty acid synthase complex is an enzyme contain several enzymes and

terminal protein called acyl carrier protein (ACP).

• Acetyl-CoA and malonyl-CoA in fatty acid synthesis are covalently linked to

SH terminals in acyl carrier protein (ACP) in fatty acid synthase complex

• Fatty acids synthesis include the following rxn:

1.Condensation: C-C (synthase)
2. 1st reduction: C=O →C-OH (reductase/NADPH)
3. Dehydration: H -C-OH→ C=C (dehydrase)
4. 2nd reduction C=C→ CH-CH (reductase/ NADPH)
ACP
 Malonyl CoA acyl
transferase MT

Acetyl CoA acyl

transferase AT

Beta keto acyl

synthase KS Beta hydroxyl acyl
dehydratase HD

Beta keto acyl Enoyl reductase ER

reductase KR
1. Condensation and reduction
In reactions 1 and 2 of fatty acid synthesis:

 Condensation by a synthase combines

acetyl-ACP with malonyl-ACP to form aceto
acetyl-ACP (4C) and CO2 (decarboxylation
and condensation)

 Reduction converts a ketone to an alcohol

using NADPH
2. Dehydration and reduction
 Dehydration forms a trans double bond (reaction 3)

 Reduction converts the double bond to a single bond

using NADPH (Reaction 4)

3. Elongation
 Palmitate (C16) is the predominant fatty acid produced. By
repeating the cycle 7 times
 Finally palmitic acid is released via hydrolysis from the
complex by the aid of thioesterase enzyme (the last
enzyme in Fatty acid synthase complex)
3. Elongation

Hydrolyzed by a thioesterase
Total cycles of fatty acid synthesis
The process of synthesis of n–numbered fatty acids is repeated until
complete fatty acid chain is formed which requires:

• Cycles number= (n/2)-1 :

Palmitic produced after 7 cycles

• The required acetyl CoA = (n/2):

Palmitate (16 C),which require 8 acetyl CoA (2C)

• NADPH= Cycles number x 2 :

To produce palmitic

 8 transported acetyl CoA , will produce 8 NADPH

 The other required 6 NADPH produced from pentose phosphate pathway PPP
 Elongation and desaturation
 Palmitate (C16) is the predominant fatty acid produced.

 Fatty acids longer than 16 carbons, those that are unsaturated, and hydroxy fatty acids are
obtained by separate processes of chain elongation, desaturation, or α-hydroxylation,
respectively occurs in mitochondria and endoplasmic reticulum (microsomal membranes).

 Palmitate is the precursor of stearate (18 C) and longer-chain saturated fatty acids, as well
as the monounsaturated acids palmitoleate and oleate.

 Mammalian hepatocytes can readily introduce double bonds at the 9 position of fatty acids
but cannot introduce additional double bonds between C-10 and the methyl-terminal end.
Thus mammals cannot synthesize linoleate, 18:2(9,12), or -linolenate, 18:3(9,12,15).

 The double bond is introduced into the fatty acid chain by an oxidative reaction catalyzed
by fatty acyl–CoA desaturase
Triglyceride biosynthesis (Lipogenesis)
• Most of the fatty acids synthesized or ingested by an organism have one of two fates:

1- incorporation into triacylglycerols for the storage of metabolic energy

2- or incorporation into the phospholipid components of membranes

• The partitioning between these alternative fates depends on the organism’s current
needs:

 During rapid growth, synthesis of new membranes requires the production of membrane
phospholipids.

 when an organism has a plentiful food supply but is not actively growing, it shunts most
of its fatty acids into storage fats triacylglycerols.
Triglyceride biosynthesis (Lipogenesis)
Triacylglycerols and glycerophospholipids such as phosphatidyl
ethanolamine share two precursors:

 (fatty acyl–CoA and L-glycerol 3-phosphate)

From fatty acids by Acyl-CoA In adipose tissue From

synthetases dihydroxyacetone phosphate
NAD-linked glycerol
3-phosphate dehydrogenase
or
in liver And kidney by
glycerol kinase
Lipogenesis steps
1- Glycerol-3- phosphate production
 in liver And kidney, glycerol 3-
phosphate is formed from
glycerol by glycerol kinase

 As Adipocytes lack glycerol

kinase In adipose tissue
dihydroxy acetone phosphate,
produced during glycolysis is
reduced in presence of
dehydrogenase enzyme giving
:glycerol-3- phosphate
2. Activation of fatty acid into fatty
acyl CoA
• Fatty acids are activated by thiokinase ( acyl
Co A synthase ) enzyme in presence of ATP,
and CoA
 3- Formation of phosphatidic acid
• Glycerol-3- p formed from step 1,
and fatty acyl CoA formed from
step 2 are esterified to produce
phosphatidic acid by glycerol-3-
phosphate acyltransferase

• Commonly but not always, the

fatty acid at C-1 is saturated and
that at C-2 is unsaturated
4. Phosphatidic acid hydrolysis
• Phosphatidic acid is hydrolysed by
phosphatase enzyme giving
diacylglycerol ,which react with other fatty
acyl CoA in presence of diglyceride acyl
transferase enzyme giving triglycerides.

• Attachment of head group (serine,

choline,ethanolamine, etc.) to phosphatidic
acid to form glycerophospholipid

• Phosphatidic acid is the precursor of

both triacylglycerols and
glycerophospholipids.
 Glycerophospholipid synthesis
• In the biosynthetic process, one of
the hydroxyls (diacyl glycerol or
head group) is first activated by
attachment of a nucleotide,
cytidine diphosphate (CDP).
• Cytidine monophosphate (CMP)
is then displaced in a nucleophilic
attack by the other hydroxyl
Chemical structure of groups (head group)
attached to Phosphate group in phospholipids
Triacylglycerol Biosynthesis in Animals Is
Regulated by Hormones
• In humans, the amount of body fat stays relatively constant over long periods, although
there may be minor short-term changes as caloric intake fluctuates

• Carbohydrate, fat, or protein consumed in excess of energy needs is stored in the form of
triacylglycerols that can be drawn upon for energy, enabling the body to withstand periods
of fasting.

• Biosynthesis and degradation of triacylglycerols are regulated such that the favored path
depends on the metabolic resources and requirements of the moment.

• Insulin promotes the conversion of carbohydrate to triacylglycerols. Severe

diabetes mellitus patients are unable to use glucose and also, fail to synthesize
fatty acids from carbohydrates or amino acids.
Triacylglycerol Biosynthesis in Animals Is
Regulated by Hormones
• If the diabetes is untreated, these individuals have increased rates of fat
oxidation and ketone body formation and therefore lose weight

• When the mobilization of fatty acids is required to meet energy needs, release
from adipose tissue is stimulated by the hormones glucagon and epinephrine

• Simultaneously, these hormonal signals decrease the rate of glycolysis and

increase the rate of gluconeogenesis in the liver

• The released fatty acid is taken up by a number of tissues, including muscle,

where it is oxidized to provide energy.