1. Ch. 33 Synthesis of Fatty acids, Triacylglycerols, Membrane lipids:
Chapt. 33
Ch. 33 Synthesis of Fatty acids, Triacylglycerols, Membrane lipids:
Student Learning Outcomes:
Describe basic steps for synthesis of fatty acids from dietary glucose (or amino acids) in the liver
Explain the role of VLDL lipoprotein particles
Explain the use of fatty acids for triglyceride synthesis
Explain the use of fatty acids for synthesis of glycerophospholipids and sphingolipids

2. Overview of lipogenesis: synthesis of triacylglycerols from glucose:
Overview lipogenesis
Overview of lipogenesis:
synthesis of triacylglycerols from glucose:
If excess calories; citrate moved from mitochondrion
Acetyl CoA, Malonyl CoA, NADPH for fatty acids
Mostly occurs in liver
In cytosol
TG packaged as VLDL
Regulated pathway
Compare b-oxidation
Fig. 1
OAA, oxaloacetate
TG, triacylglycerol

3. Overview Fate of VLDL-TG
Overview: fate of VLDL-Triacylglycerols
TG is digested by LPL (lipoprotein lipase) on surface of capillaries (see Ch. 32)
FA for energy generation (muscle)
FA for storage (reform TG in adipose)
Glycerol returns to liver
See also Ch. 2
Fig. 2

4. Overview – membrane lipids
Glycerophospholipids – diverse head groups
Plasmalogen – platelet activation factor (ether link)
Sphingolipid – serine not glycerol backbone
Glycolipid – no PO4
See also Figs. 5.19, 20
Fig. 3

5. I. Fatty acid synthesis from excess carbohydrates
Glucose to cytosolic Acetyl CoA
Two paths from pyruvate (gluconeogenesis, TCA)
Reciprocal inhibition/stimulation depends on [Acetyl CoA]
OAA + Acetyl CoA → citrate (1st step TCA)
Citrate transported to cytosol
Cleave to OAA + Acetyl CoA
[PDH is only in mitochondrion;
Acetyl CoA can’t cross membrane]
Fig. 4

6. B. Citrate in cytosol to Acetyl CoA:
Citrate lyase cleaves → Acetyl CoA and OAA
NADPH is required for fatty acid synthesis:
Some is made from Pentose Phosphate pathway
Other from recycling OAA back to pyruvate:
Reduce (uses NADH); recall TCA reversible reaction
Oxidative decarboxylate (makes NADPH)
Figs. 5,6
↑, inducible enzymes

7. Fatty acid synthesis needs Acetyl CoA, NADPH
in the cytoplasm
NADPH from Pentose
phosphate pathway
NADPH from Malic enzyme
Acetyl CoA from citrate lyase
Fig. 7

8. B. Acetyl CoA to Malonyl CoA
B. Conversion of Acetyl CoA to Malonyl CoA
One Acetyl CoA and many Malonyl CoA are needed
Malonyl CoA is immediate donor of the 2-C units
Acetyl CoA carboxylase requires biotin and ATP
Acetyl CoA carboxylase is rate-limiting, highly regulated
AMP levels signal fasting ([AMP]/[ATP] sensitive
Figs. 8,9

9. C. Fatty acid synthase complex
Sequentially adds 2-C units from 3-C malonyl CoA
2 reduction reactions after each addition (NADPH)
16-C Palmitate is typical product
FAS is large enzyme: 2 subunits (one polypeptide each) with 7 catalytic activities and ACP domain
ACP – acyl carrier protein segment (Ser) is joined to a derivative of coenzyme A:
Oriented with phosphopantetheinyl SH group (P-SH) of one subunit near Cys SH group on other
Fig. 10

10. Fatty Acid synthase – 1st steps
Fatty acid synthase – beginning
1. Acetyl CoA onto ACP P-SH group
2. Acetyl CoA transfers to Cys –SH of other
3. This Acetyl CoA will become the w (last) C of the fatty acid (i.e. carbon 16 of palmitate)
4. Malonyl CoA attaches to ACP SH
5. Malonyl CoA releases CO2; 2-C unit condenses with the Acetyl CoA, and a 4-C product is produced on ACP (C 13-16)
Fig. 11*

11. Fatty Acid synthesis Reduction reactions
Reduction reactions convert b- ketoacyl group
NADPH is reducing agent
C=O → HCOH
HCOH → C=C
C=C → CH2-CH2
The 4-C unit will transfer to the SH of the Cys on other subunit
Sort of opposite to b-oxidation
Costs 1 ATP to form Malonyl CoA
Costs 2 NADPH per addition
Fig. 12

12. Fatty Acid synthesis to palmitate (C16)
Fatty acid synthesis: cycles of 2-C addition
From 1 2-C Acetyl CoA and rest 3-C malonyl CoA
End C was first added (last unit is the COOH end)
Forms on ACP, then moves to Cys SH of other subunit
Cleavage at end
2 NADPH/cycle
1 ATP/cycle
1 CO2 added/ released
Fig. 13

13. New fatty acid is not reoxidized in liver
Inhibition of carnitine acyl transferase CPT1
Longer fatty acids are made in Smooth ER by similar reactions involving malonyl CoA (Fig. 15)
Other enzymes desaturate the FA-CoA to form the unsaturated derivatives
Use O2, NADH (Figs. 16, 17)
Fig. 14

14. Triacylglycerol synthesis
II. Synthesis of TG, VLDL
Liver: phosphatidic acid + FA-CoA → Triacylglycerol (TG), made in smooth ER
Adipose cells do not have glycerol kinase
VLDL packages TG, phospholipids, cholesterol and proteins (apoB-100)
Processed in Golgi, secreted
More dense than chylomicrons (less TG)
Fig. 18, 19

15. Summary of VLDL from liver
Summary VLDL from glucose in liver:
VLDL secreted into blood
VLDL will get apoCII and ApoE from HDL
Figs. 20, 21

16. Fed Fate of VLDL triglycerols
IV. Fate of VLDL triglycerols in Fed state:
LPL lipase cleaves to FA + glycerol (like chylomicron)
ApoCII activates LPL
[Muscle LPL low Km, grabs FA]
IDL & LDL products (Ch. 34)
Fig. 22

17. Fasting releases FA from Adipose tissues
V. Fasting releases FA from adipose tissue
Insulin low, glucagon high; cAMP → PKA….
Active Hormone Sensitive Lipase-P is TG lipase
FA travel in blood bound to serum albumin
Muscle oxidizes FA for energy
Liver makes ketone bodies
from Acetyl CoA
Liver uses glycerol for
gluconeogenesis
Fig. 23

18. VII. Metabolism of glycerophospholipids, sphingolipids
VII. Glycerophospholipids, sphingolipids:
Components of cell membranes, blood lipoproteins, bile and lung surfactants (see also Ch. 5)
glycerol backbone, serine (sphingosine)
Fig. 25

19. A. Synthesis of glycerophospholipids
Similar to TG: Glycerol-3-phosphate + 2 FA →phosphatidic acid
Then two paths to addition of head group; both use CTP
Fig. 26

20. Some glycerophospholipids
Phosphatidic acid has PO4 on 3rd C of glycerol
Slightly different paths for synthesis of two groups
Both use CTP
Fig. 27,28

21. Phospholipases degrade glycerophospholipids
B. Degradation of glycerophospholipids
Different phospholipases attack different bonds
Enzymes in cell membranes, lysosomes
PL C cleaves PIP2 → DAG + IP3
PL D → phosphatidic acid + alcohol head group
PL A2 cleaves off FA at C2 (often arachidonic, signaling)
PLA2 also repairs damage by free radicals to C=C)
Fig. 30

22. Synthesis of sphingolipids: Intercell communication
AB blood groups
Receptors for viruses
Ceramide is central molecule
Serine basis
Fatty acid addition, release CO2
Reduction
Other fatty acid to NH2 group
Oxidation
Fig. 31
PLP = pyridoxal PO4

23. Synthesis of some sphingolipids
Sphingolipids are based on ceramide:
Addition of head groups to –OH (from serine)
Addition of sugars uses UDP-sugar
Degraded in lysosome
Deficiency diseases
Fig. 32

24. Adipocytes can also make hormones:
other
Adipocytes can also make hormones:
Leptin – identified as helping ob/ob obese mice lose weight
Binds JAK receptor/ signals through sTAT
Adiponectin – maybe linked to insulin resistance
AMP kinase, PPARg, enhanced fatty oxidaiton
Metabolic syndrome associated with obesity:
Insulin resistance, obesity, altered blood lipid levels
High risk for type 2 diabetes, cardiovascular disease
Read description in text (Fig. 35)

25. Fatty acids synthesized mainly in liver, from glucose
Key concepts
Key concepts:
Fatty acids synthesized mainly in liver, from glucose
Glucose to pyruvate in mitochondrion, forms Ac CoA, OAA, which form citrate
Citrate in cytosol then to Ac CoA, malonyl CoA
Fatty acid synthesis involve series 2-C additions from malonyl CoA to the w-C of Ac CoA onto FA synthase.
Costs 2 NADPH and 1 ATP per cycle addition
Fatty acids packaged as TG in liver as VLDL with proteins and other lipids; digested by LPL on capillaries and FA enter cells (oxidized or stored)
Glycerophospholipids similar synthesis
Spingolipids from sphingosine (serine + FA)

26. Review question: Review question
3. A patient with hyperlipoproteinemia would be most likely to benefit from a low-carbohydrate diet if the lipoproteins that are elevated in blood are which of the following?
Chylomicrons
VLDL
HDL
LDL
IDL