1. Lipogenesis & Lipolysis

2. Lipogenesis Triacylglycerol synthesis
Definition:
Lipogenesis is the synthesis of TAG from fatty acids and glycerol.
Site:
Sub-cellular site: cytoplasm
Organ (tissue) site: liver (primary site), adipose tissue, lactating mammary gland, kidney
Esters of glycerol with three fatty acids
Functions of Triglyceride
Main stored from of energy in adipose cells. Energy: 9kcal/gram

3. Steps of Lipogenesis
Synthesis of glycerol phosphate (activation of glycerol):

4. Synthesis of acyl-CoA (activation of fatty acids):
Thiokinase
CoA
ATP AMP+Pi
Fatty acid > acyl CoA
Acyl transferases catalyes the transfer acyl groups
Fates of the formed TAG
In liver: TAG VLDL tissues
In adipose tissue: TAG stored as depot fat
Regulation of lipogenesis
Insulin stimulates lipogenesis
Adipocytes can take glucose only in the presence of insulin
Insulin stimulate glycolysis which supplies glycerol phosphate
Anti-insulin hormones inhibit lipogenesis

5. Lipolysis
is the hydrolysis or breakdown of triacylglycerol in adipose tissue to glycerol and 3 fatty acids
It requires enzymes called lipases which are present in the adipose tissue.
Site:Sub-cellular site: cytoplasm
The hydrolysis of triacylglycerol is initiated by
hormone sensitive lipase.
HSL is Hormonally regulated

6. Regulation of lipolysis
Hormone-sensitive lipase (HSL) is activated when phosphorylated by cyclic AMP-dependent protein kinase
Epinephrine & other anti-insulin hormones stimulate lipolysis during fasting, stress & hypoglycaemia by
activation of adenylate cyclase forming cAMP
Insulin inhibits lipolysis by
Inhibiting adenylate cyclase enzyme
Stimulating phosphodiesterase
Stimulating phosphatase enzyme

7. Lipid Metabolism in Fat Cells: Fed State Starved State
Insulin
Stimulates up-take of glucose by Adipocytes
stimulates glycolysis
increased glycerol phosphate synthesis
increases esterification
inactivates HSL
net effect: TG storage
Glucagon, epinephrine
activates HSL
net effect: TG mobilization and increased FFA
inhibit lipogenesis

8. FATTY ACIDS SYNTHESIS Fatty acid synthase multienzyme complex.
Definition: Synthesis of saturated fatty acids
Product: palmitate (16 c)
Site:
Sub-cellular site: cytoplasm
Organ (tissue) site: liver, lactating mammary gland, adipose tissue & kidney
Main requirements:
Acetyl CoA (Active Acetate)
Acetyl CoA carboxylase enzyme
ATP for activation & fixation of CO2 in the synthesis of malonyl CoA from acetyl CoA
NADPH
Fatty acid synthase multienzyme complex.
It is a dimer. Each unit contains 7 enzymes and a protein (acyl carrier protein)
ACP Fatty Acid Synthase β-Ketoacyl synthase
β-Ketoacyl synthase Fatty Acid Synthase ACP SH

9. Steps of Fatty acid synthesis
Translocation of acetyl CoA from mitochondria to cytoplasm (Citrate shuttle)
B Cytoplasmic pathway for fatty acid synthesis:
Carboxylation of acetyl CoA (2 carbon atoms) to malonyl CoA by acetyl CoA carboxylase (ACC)
Formation of palmitate (16 C) by Fatty acid synthase multienzyme complex.

10. Cytoplasmic pathway for fatty acid synthesis:
1- Carboxylation of acetyl CoA by Acetyl CoA Carboxylase
‘first reaction’ of fatty acid synthesis
This is the irreversible regulatory step in fatty
acid synthesis
malonyl-CoA serves as activated donor of acetyl groups in FA synthesis

11. Thioesterase 2- Formation of palmitate (16 C):
All the next steps are catalyzed by Fatty acid synthase
Priming reactions (Transacetylases)
(1) Condensation Rxn
(2) Reduction Rxn
(3) Dehydration Rxn
(4) Reduction Rxn
Thioesterase
The overall reaction for palmitate synthesis:
1 Acetyl CoA+7 Malonyl CoA+14(NADPH+H†)+7ATP Palmitate(16C)+8CoA+14NADP†+7(ADP+Pi)+7H2O

12. REGULATION OF FATTY ACID SYNTHESIS
Acetyl CoA Carboxylase
Citrate
Malonyl CoA
Palmitoyl CoA
Insuline
Glucagon
Epinephrine -
I- short-term regulation of acetyl CoA carboxylase
High-calorie, high- carbohydrate diets
Low-calorie diet or fasting +
II- long-term regulation of acetyl CoA carboxylase
Acetyl CoA > Malonyl CoA
Allosteric
Hormonal

13. Catabolic Pathway Of FA Beta Oxidation Of Fatty Acids

14. Beta Oxidation of Fatty acids
Beta Oxidation is the process where energy is produced by degradation of fatty acids to acetyl-CoA units
The process of fatty acid oxidation is termed b oxidation since it occurs through the sequential removal of 2-carbon units (as acetyl-CoA) by oxidation at the b-carbon position of the fatty acyl-CoA molecule.
Importance of b-oxidation
Energy production
Acetyl-COA production

15. β -oxidation takes place in Mitochondria 1
β -oxidation takes place in Mitochondria
→ Fatty acids which are participating in β-oxidation undergo activation to form Fatty acyl CoA
→ Activation of fatty acid takes place in CYTOPLASM, requires 2 high energy bonds and enzyme is Thiokinase or fatty acyl Co A synthetase.

16. N(CH3)3 CH2 H-C-OH COO- Carnitine FA~CoA HS-CoA Carnitine FA~Carnitine
Transport of acyl CoA into the mitochondria ( rate-limiting step)
The activated fatty acids which are present in CYTOPLASM
enters into MITOCHONDRIA with the help of CARNITINE CARRIER.
N(CH3)3
CH2
H-C-OH
COO- +
Carnitine
FA~CoA
Acyl transferase I
HS-CoA
Carnitine
FA~Carnitine
CYTOPLASM
Translocase
FA~Carnitine
Carnitine
THE MATRIX
FA~CoA
HS-CoA
Acyl transferase II

17. β – oxidation proper There are 4 steps in β C– oxidation
Step I – Oxidation by FAD linked dehydrogenase
Step II – Hydration by Hydratase
Step III – Oxidation by NAD linked dehydrogenase
Step IV – Thiolytic clevage Thiolase

18. Beta Oxidation

19. Beta Oxidation

20. Beta Oxidation
Palmitic (16 c)

21. -Oxidation and ATP Activation of a fatty acid requires: 2 ATP
One cycle of oxidation of a fatty acid produces:
1 NADH ATP
1 FADH ATP
Acetyl CoA entering the citric acid cycle produces:
1 Acetyl CoA 12 ATP
Palmitic acid (16 C) needs 7 cycles of beta-oxidation, which gives rise to
8 acetyl Co A x 12 = 96 ATP
7 FADH2 x = 14 ATP
7 NADH x = 21 ATP
Total ATP
In initial activation Palmic acid → Palmitoyl Co A requires 2 high energy phosphates, so net is 131 – 2 = 129 ATP

22. β- oxidation of odd number fatty acids
Odd number fatty acids are oxidized by β-oxidation until the final 3 carbons propionyl CoA is produced.
So, β- oxidation of odd number fatty acid gives: (n) acetyl CoA + 1 propionyl CoA
Propionyl CoA is converted to succinyl CoA which can enter the TCA cycle

23. Ketone Bodies A special source of fuel and energy for certain tissues
Some of the acetyl-CoA produced by fatty acid oxidation in liver mitochondria is converted to acetone, acetoacetate and -hydroxybutyrate
These are called "ketone bodies"
Source of fuel for brain, heart and muscle
Ketogenesis increases in fasting , diabetes and starvation 19

24. Oxidation of Ketone Bodies for Energy
Most tissues can oxidize ketone bodies
-requires mitochondria
Conditions that increase KB synthesis and oxidation
Length of fasting (> 3 days)
Low carb diets
Untreated Type 1 diabetes
Diabetic ketoacidosis
Liver synthesizes KB but can not oxidize them: liver lacks CoA transferase
ENERGY PRODUCTION FROM OXIDATION OF
-HYDROXYBUTYRATE
4/29/11

25. Lipid transport

26. Plasma Lipoproteins (Structure)
All the lipids contained in plasma, including fat, phosphalipids, cholesterol, cholesterol ester and fatty acid, exist and transport in the form of lipoprotein
Non-covalent assemblies of lipids and proteins
LP core
Triglycerides
Cholesterol esters
LP surface
Phospholipids
Proteins
cholesterol
Function as transport vehicles for triacylglycerols and cholesterol in the blood

27. CM Major apoB 48 apoB 100 apoB 100 apoA-I Protein Major TG TG CE CE
Lipoprotein Nomenclature, Composition and seperation CM
VLDL
LDL
HDL
Major apoB apoB apoB apoA-I
Protein
Major TG TG CE CE
Lipid
Electrophoresis method:
- Lipoprotein fast
pre -Lipoprotein
-Lipoprotein
CM (chylomicron) slow
2. Ultra centrifugation method：
high density lipoprotein (HDL) high
low density lipoprotein ( LDL)
very low density lipoprotein ( VLDL)
CM (chylomicron ) slow

28. Lipids (Triacylglycerols) are Transported as Lipoproteins
Intestinal Mucosa (Exogenous Lipids) Chylomicrons
Liver (Endogenous Lipids)
VLDL (very low density lipoproteins)

29. Chylomicrons Synthesized in small intestine
Transport dietary lipids (exogenous TG)
98% lipid, large sized, lowest density
Apo B-48
Receptor binding
Apo C-II
Lipoprotein lipase activator
Apo E
Remnant receptor binding
Nascent chylomicron (B-48)
Mature chylomicron (+apo C & apo E)
Lipoprotein lipase
Chylomicron remnant
Apo C removed
Removed in liver

30. Very Low Density Lipoprotein (VLDL)
Synthesized in liver
Transport endogenous triglycerides
90% lipid, 10% protein
Apo B-100
Receptor binding
Apo C-II
LPL activator
Apo E
Remnant receptor binding
Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
LPL hydrolyzes TG forming IDL
75% of IDL removed by liver
25% of IDL converted to LDL by hepatic lipase

31. Blood Cholesterol
Is both consumed (exogenous) and produced by the liver (endogenous).
Endogenous production increases with high ingestion of Saturated fat
Found ONLY in animal products

32. Acetyl CoA is the source of all carbon atoms in cholesterol
Acetoacetyl CoA
CoA
Acetyl CoA
Inhibition
β -hydroxy- β- methylglutaryl CoA
HMG-CoA
reductase
Mevalonate
Squalene
Cyclization
Farmesyl pyrophosphate

33. Low Density Lipoproteins (LDL - Bad)
Formation site: from VLDL in blood, but a small part is directly released from liver
Function: transport cholesterol from liver to the peripheral tissues.
Carries aprox. 50% of blood cholesterol. containing only apo B-100.
LDL concentration in blood has positive correlation with incidence of cardiovascular diseases.
Fates of cholesterol in the cells
1. Incorporated into cell membranes.
2. Metabolized to steroid hormones.
3. Re-esterified and stored.
4. Expulsion of cholesterol from the cell, and transported by HDL and finally excreted through liver.

34. High Density Lipoproteins (HDL – Good)
Formation site: liver and intestine
Function: transport cholesterol from peripheral tissues to liver (reverse cholesterol transport)
Reservoir of apoproteins
Contain  protein,  Cholesterol
Protects against heart disease
Apo A
Activates lecithin- cholesterol acyltransferase (LCAT)
Apo C
Activates LPL
Apo E
Remnant receptor binding
Uptake of cholesterol from peripheral tissues
Esterification of HDL-C by LCAT
Transfer of CE to (IDL and CR)
removal of CE-rich remnants by liver
converted to bile acids and excreted

35. Functions of apolipoproteins
a . To combine and transport lipids. b . To regulate lipoprotein metabolism. apo A II activates hepatic lipase（HL） apo A I activates LCAT apo C II activates lipoprotein lipase（LPL） c. To recognize the lipoprotein receptors.

36. Apolipoproteins