Lipid metabolism is the processing of lipids for energy use, energy storage, and structural component (Cholesterol & lipoproteins) production. Lipids are digested by lipase enzymes in the GI tract (with the help of bile acids) and are absorbed directly through the cell membrane. Free fatty acids are then resynthesized into triacylglycerols (TAGs) in the enterocytes. Finally, lipid components are repackaged into chylomicrons and transported throughout the body for use or storage.

1. Lipid Metabolism in Health & Diseases
Rajendra Dev Bhatt, PHD Scholar
Asst. Professor
Clinical Biochemistry & Laboratory Medicine
Dhulikhel Hospital-Kathmandu University Hospital
Fellow: Translational Research (2018-2022) in CVD in Nepal, NHLBI & NIH, USA

2. Review of lipids
The lipids are a heterogeneous group of
compounds, including fats, oils, steroids, waxes, and
related compounds, which are related more by their
physical than by their chemical properties. They
have the common property of being (1) relatively
insoluble in water and (2) soluble in nonpolar
solvents such as ether and chloroform.

3. Lipids / fats in the our Body
• Fatty Acids (Synthesis and oxidation)
• Cholesterol
• Chylomicrons
• High-Density Lipoprotein (HDL-C)
• Low-Density Lipoprotein(LDL-C)
• Very-Low-Density Lipoprotein ( VLDL-C)
• Intermediate-Density Lipoprotein(IDL-C)

4. Lipid Metabolism
• Lipid metabolism is the processing of lipids for energy use,
energy storage, and structural component (Cholesterol &
lipoproteins) production. Lipids are digested by lipase
enzymes in the GI tract (with the help of bile acids) and are
absorbed directly through the cell membrane. Free fatty
acids are then resynthesized into triacylglycerols (TAGs) in
the enterocytes. Finally, lipid components are repackaged
into chylomicrons and transported throughout the body for
use or storage. Within target cells, fatty acids can be
synthesized from acetyl-CoA molecules, and TAGs can be
synthesized from the fatty acids and a glycerol backbone.

5. Synthesis Of Fatty Acids

6. Fatty Acids
• A fatty acid contains a long hydrocarbon chain and a terminal
carboxylate group. The hydrocarbon chain may be saturated
(with no double bond) or may be unsaturated (containing
double bond).
Fatty acids can be obtained from-
Diet
Adipolysis
De novo synthesis

7. De novo synthesis of Fatty Acids
(Lynen's spiral Pathway)
Fatty acids are synthesized by an extra
mitochondrial system
This system is present in many tissues, including liver,
kidney, brain, lung, mammary gland, and adipose tissue.
Acetyl-CoA is the immediate substrate, and free
palmitate is the end product.
Its cofactor requirements include NADPH, ATP, Mn2+,
biotin, and HCO3
– (as a source of CO2).

8. Beta-oxidation Fatty acid synthesis
Site Mitochondria Cytoplasm
Enzymes Present as independent proteins Multienzyme complex
Sequential units 2C units released as Acetyl CoA 2C added as Malonyl CoA(3C)
Co-enzymes NAD and FAD NADPH
Transport Carnitine Citrate
End product Acetyl CoA Palmitate
Lynen's spiral / Lipogenesis
It is not a reversal of oxidation.
Difference b/w synthesis and breakdown of fatty acids are :-

9. Subcellular organelle - Cytoplasm (extra-mitochondrial)
Source of carbon atoms - Acetyl CoA
Source of reducing equivalent - NADPH
Source of energy - ATP
 Site :-
Liver, adipose tissue, kidney, brain and mammary glands
Source of fatty acids :-
Exogenous - Diet (major)
Denovo / Endogenous - Pathway operates – excess of caloric in
the diet – fatty acids are synthesized – and stored as
Triacylglycerol (TAG)

10. • Stages of fatty acids synthesis
 Transport of Acetyl CoA and NADPH into cytoplasm.
 Conversion of Acetyl CoA to Malonyl CoA.
 Reactions of Fatty acid synthase complex.

11. Transport of Acetyl CoA to cytoplasm
 Acetyl CoA is produced in the mitochondria by the oxidation of pyruvate
and fatty acids, degradation of carbon skeleton of ketogenic amino acids.
 Because it is impermeable, Acetyl CoA is converted to citrate and
transported to cytoplasm.
 This transport is coupled with the cytosomal production of NADPH and
CO2 which is also required for FA synthesis.

12. Acetyl-CoA
Pyruvate
AAs
Fatty acids
PDH
Mitochondria Cytoplasm
Oxaloacetate
Citrate
ATP Citrate
synthase
Malate
NAD+
NADH+H
Malate DH
Pyruvate
NADP+
NADPH+H
Malic
enzyme
Tricarboxylic
acid transporter
Citrate
Acetyl-CoA
Oxaloacetate
ATP
Citrate
lyase
Malate
NAD+
NADH+H
Malate DH
Pyruvate
NADP+
NADPH+H
CO2

13. Conversion of Acetyl CoA to Malonyl CoA / Carboxylation of
Acetyl CoA
(3C) Malonyl-CoA
CO2
ADP+Pi
CH3-C-SCoA
O
=
(2C) Acetyl-CoA
-OOC-CH2-C-SCoA
O
=
Biotin
Acetyl CoA carboxylase
+
Acetyl CoA carboxylase is the rate limiting enzyme of this pathway.
ATP
The elongation of the fatty acid occurs by addition of 2 carbon atoms at a
time. But the 2-carbon units are added as 3-carbon, malonyl units

15. Fatty Acid Synthase (FAS) Complex
• exists as a multi-enzyme complex
• The enzymes form a dimer with identical subunits
• Each subunit is organized into 3 domains with 7 enzymes
• Subunits independently operate & both synthesize FA simultaneously
subunits lie in Antiparallel (head to tail) orientation
 1st Domain or Condensing Unit - initial substrate binding site
Beta-keto acyl synthase or Condensing enzyme (CE); Acetyl transferase (AT)
and Malonyl trans acylase (MT)
 2nd Domain or Reduction Unit - Dehydratase (DH); Enoyl reductase
(ER); Beta-keto acyl reductase (KR) and Acyl carrier protein (ACP)
 3rd Domain or Releasing Unit - release the FA synthesised.
Thio-esterase (TE) or Deacylase

16. • ACP - polypeptide chain having a phospho-pantotheine group, to which
the acyl groups are attached in thioester linkage.
• ACP acts like the CoA carrying fatty acyl groups
• Eukaryotes - ACP is a part of FAS complex
• Prokaryotes – FAS complex + separate acyl carrier protein
• Advantages of Multi-enzyme Complex
• Intermediates of the reaction can easily interact with the active sites of
the enzymes.
• One gene codes all the enzymes; so all the enzymes are in equimolecular
concentrations.
• So the efficiency of the process is enhanced.

17. FAS complex
Cys
Cys
4’-phospho-
pantetheine
4’-phospho-
pantetheine
SH
SH
SH
SH
Subunit
division
Thioesterase
ACP
-SH group of
phosphopantetheine
of one subunit is in
close proximity
to the -SH of
cysteine residue of
CE of the other
subunit
1
2
Thioesterase
CE
AT
MT
Acetyl
transacylase
Malonyl
transacylase
Ketoacyl
synthase
DH
ER
KR

19. sivaranjani

32. Reactions of fatty acid synthase complex
CH3-C-SCoA
O
=
Acetyl-CoA
CoA-SH
ACP SH
Cys SH
ACP S
Cys SH
-C-CH3
O
=
ACP SH
Cys S-C-CH3
O
=
Acetyl S-enzyme
Acetyl S-ACP
FAS complex
Acetyl CoA
transacylase
Transfer of
acetyl to cys
 2C of acetyl CoA is transferred
to ACP of FAS by Acetyl CoA-
ACP transacylase.
 The acetyl unit is then
transferred from ACP to
cysteine residue of the Enzyme
 Thus ACP site falls vacant
1

33. Malonyl transacylase transfer malonate
from malonyl CoA to ACP to form acetyl-
malonyl enzyme
ACP SH
Cys S-C-CH3
O
=
Acetyl S-enzyme
Malonyl-CoA
-OOC-CH2-C-SCoA
O
=
CoA-SH Malonyl trasacylase
ACP S
Cys S-C-CH3
O
=
-C-CH2-COO
O
=
β-Ketoacyl-ACP
CO2
β-Ketoacyl synthase / CE
ACP S
Cys S
-C-CH2
O
=
Acetyl-Malonyl E
condensing enzyme or keto acyl synthase
condenses Acetyl-S-Cys and malonyl-S-ACP
-C-CH3
O
=
Condensation reaction
2
3

34. β-Ketoacyl-ACP
ACP S
Cys SH
-C-CH2
O
=
-C-CH3
O
=
NADP+
NADPH+H+
β-Ketoacyl reductase
ACP S
Cys SH
-C-CH2
O
= -C-CH3
OH
β-Hydroxyacyl-ACP
H2O
Trans-enoyl-ACP
β-hydroxyacyl dehydratase
ACP S
Cys SH
-C-CH
O
=
CH-CH3
ketoacyl ACP is reduced by NADPH dependent
beta-keto acyl reductase to form beta-hydroxy
fatty acyl ACP
β-Hydroxyacy ACP undergoes dehydration.
A molecule of water is eliminated & a double
bond is introduced b/w α and β carbons.
Reduction
Dehydration
4
5

35. NADP+
NADPH+H+
Trans-enoyl-ACP
ACP S
Cys SH
-C-CH
O
=
CH-CH3
Acyl-ACP / butyrylACP
ACP S
Cys SH
-C-CH
O
=
CH2-CH3
Enoyl reductase
Transfer of C chain from ACP to cys-SH
ACP SH
Cys S-C-CH
O
=
CH2-CH3
Acyl-S-enzyme
4C unit attached to ACP is
butyryl group
Reduction
6

36. Palmitate (16C)
Palmitoyl Thioesterase
reactions of 2-6 are repeated 6 times
ACP SH
Cys S-C-CH
O
=
CH2-CH3
Acyl-S-enzyme
ACP S -
Cys SH
ACP SH
Cys SH
CH3-CH2
-(CH2)13-COO-
+
7

37. Summary of palmitate synthesis
• End product –(16C) Palmitate
• 2C - Acetyl CoA directly
• 14C - Malonyl CoA
• Over all reaction :
Palmitoyl-coA
CO-S-coA
CH3
1
2
3
4
5
6
7
8
9
10
12
14
16
15 13 11
8 Acetyl-coA = Acetyl-CoA + 7 malonyl-CoA
CH3-CO-SCoA
14 NADPH+H+
7 Cycles of
Fatty acid synthesis
7 ATP
7 ADP+Pi
14 NADP+
6 H2O

38. Regulation
Acetyl CoA carboxylase enzyme controls a committed step in fatty acid synthesis. This
enzyme exists as an inactive monomer or an active polymer. Citrate promotes
polymer formation, hence increases FA synthesis. Palmitoyl CoA and malonyl CoA
causes depolymerisation of the enzyme and inhibit FA synthesis.
Hormonal influence
• Glucagon, epinephrine & norepinephrine inactivate the enzyme by
cAMP dependent phosphorylation and inhibits FA synthesis
• Insulin dephosphorylates & activates the enzyme and promotes FA
synthesis.

39. Dietary Regulation:
High carbohydrate and fat free diet increases the
synthesis of Acetyl CoA carboxylase and FA synthase,
which promotes FA synthesis.
Fasting and high fat diet decreases FA production.
NADPH influences FA synthesis.

40. Summary of FA synthesis
Site: Liver, Adipose tissue, Mammary gland during lactation
Localization:  Cytoplasm (up to C16)
Enzymes:  Acetyl-CoA-carboxylase (HCO3
-
- source of CO2, biotin, ATP)
 Fatty acid synthase (NADPH ,CoA)
Primary substrate:  Acetyl-CoA
Final product:  Palmitate
(always in excess calories)

41.  2-6 Rxn are repeated by 2C in each cycle to form chain
length C16 (palmitate)
 Palmitate,is a precursor of saturated and unsaturated FA:
 Saturated FA (> C16) elongation systems
 Unsaturated FA (=) desaturation systems

42. 1. In what compartment does the de novo fatty acid
synthesis occur?
a. Mitochondria
b. Peroxisome
c. Endoplasmic reticulum
d. Cytosol
Answer: Cytosol

43. 2. What is the precursor for fatty acid synthesis?
a) Acetyl CoA
b) Propionyl CoA
c) Succinyl CoA
d) Acetoacetyl CoA
Answer: Acetyl CoA

44. 3. Which of the following is true regarding the transport
of Acetyl CoA?
a) Acetyl CoA is diffused from the mitochondrial membrane
b) Acetyl CoA is transported by its specific transporter
protein
c) Acetyl CoA is converted into pyruvate, enters into the
cytosol and acetyl CoA is regenerated
d) Acetyl CoA is converted into citrate, enters into the cytosol
and acetyl CoA is regenerated.
Answer: D

45. 4. What is the allosteric regulator of acetyl CoA
carboxylase?
a) Fatty acid
b) ATP
c) Citrate
d) Acetyl CoA
Answer:Citrate

46. 5. Which of the following event inactivates acetyl CoA
carboxylase?
a. ADP-Ribosylation
b. Glycosylation
c. Phosphorylation
d. Farnesylation
Answer: Phosphorylation

47. THANK YOU