this chapter looked at the synthesis, processing, and packaging of fatty acids in the liver and adipose tissue. the first section looked at where the precursors for fatty acid synthesis come from: acetyl CoA is required for fatty acid synthesis and is created in the mitochondria from pyruvate via pyruvate dehydrogenase, then combined with oxaloacetate to form citrate. citrate is shuttled out into the cytosol and cleaved back into acetyl CoA and oxaloacetate (which is then recycled back to pyruvate).
the synthesis of fatty acids begins with the conversion of acetyl CoA to malonyl CoA via the enzyme acetyl CoA carboxylase. (recall from chapter 23 that malonyl CoA is an inhibitor of beta oxidation of fatty acids). this is the rate limiting step of fatty acid synthesis and is regulated by a number of different factors. first, it is inhibited by the products of fatty acid synthesis, malonyl CoA, palmitate, and palmitoyl CoA, and also stimulated by a buildup of reactants- acetyl CoA, citrate, glucose. secondly, acetyl CoA carboxylase is inhibited by a high insulin level, which activates a phosphatase that inactivates the enzyme, while stimulated by high AMP levels (signaling the need for more energy), which activates a protein kinase that activates the enzyme.
the steps for the synthesis of fatty acids:
1. an acetyl moeity attaches to the sulfhydryl group (short arm) of the fatty acid synthase complex and then is transferred to the cysteine-sulfhydryl group (long arm).
2. a malonyl moeity attaches to the short arm and undergoes a condensation reaction with the acetyl CoA from step 1.
3. the keto-acyl that is formed in step two is reduced to an alcohol, forms a double bond via removal of water, and reduced again to remove the double bond. the net result of steps 2 and 3 is the addition of 2 carbons to the ∆-end of the fatty acid chain.
4. the keto-acyl chain is transferred back to the long arm, and another malonyl moeity is attached to the short arm.
5. the keto-acyl chain and malonyl combine via a condensation reaction and the elongation process continues.
6. when the fatty acyl chain reaches 16 carbons, hydrolysis occurs and palmitate is released.
palmitate can then be elongated and desaturated. elongation occurs in a process similar to fatty acid synthesis, except the fatty acyl chain attaches to coenzyme A rather than the ACP sulfhydryl group. a common elongation reaction is that of palmityl CoA to stearyl CoA (C18). desaturation occurs in the endoplasmic reticulum and requires molecular oxygen, NADH, and cytochrome b5. in humans, this process can only occur up to carbon ∆9; thus carbons ∆10 through ∆16 on the palmitate produced by fatty acid synthesis can not be de-saturated. omega 3 and 6 fatty acids fit into this category (3 and 6 carbons from the opposite end correspond to carbons ∆14 and ∆11) and thus must be obtained from plant oils and fish oils. plant oils contain linoleic acid and alpha-linolenic acid, both of which are used as precursors for eicosanoids synthesis.
the next section talks about what happens to fatty acids after they are synthesized in the liver. fatty acids are then combined into triacylglycerols- the glycerol backbone is created either through phosphorylation of glycerol via glycerol kinase, or through the glycolytic intermediate G3P. the process of forming a triacylglycerol is as follows: two fatty acyl CoA's are combined with a glycerol 3-phosphate molecule to form phosphatidic acid. phosphatidic acid is then dephosphorylated to form a diacylglycerol, to which another fatty acyl CoA is added, forming a triacylglycerol. the TG's are then packaged into very-low-density-lipoproteins (VLDL), which are similar to chylomicrons (recall from lipid digestion) in that they are hydrophilic droplets containing TG's, cholesterol, and apoproteins. The nascent VLDL is released into the bloodstream, where it matures upon receiving apoproteins CII and E from a HDL molecule.
the fate of VLDL's is discussed: in circulation, VLDL encounters the enzyme lipoprotein lipase (LPL), located on the endothelium basement membrane, which cleaves the TG's in the VLDL's into glycerol and fatty acids. the LPL in skeletal muscle has a high affinity for the TG's, allowing skeletal muscle to metabolize fatty acids even if the concentration is low. in contrast, the LPL in adipose tissue has a lower affinity for the TG's, and is consequently activated during the fed state when the concentration of VLDL's in circulation is high. once the TG's have been removed from the VLDL, it becomes an intermediate or low density lipoprotein. in adipose tissue, the glycerol backbone is released back into the bloodstream and back to the liver to be recycled, since adipose tissue does not have the glycerol kinase necessary to reuse glycerol for TG synthesis. during the fed state, the high insulin/glucagon ratio stimulates synthesis of LPL, ushering fatty acids into the adipose cells, where they are repackaged into TG's in a similar fashion to what was described above. in the fasting state, a glucagon sensitive lipase cleaves the stored TG's into fatty acids, which are then released into circulation, where they can be metabolized for energy (see chapter 23 notes).
questions
introduction...
1. when are fatty acids synthesized?
2. where does fatty acid synthesis take place?
3. where is the fatty acid synthase complex located?
4. what are the two possible fates for pyruvate in the mitochondria?
5. describe the production of acetyl coA for fatty acid synthesis.
6. why does acetyl CoA need to be produced in the mitochondria? why is it converted into citrate?
7. where does the NADPH required for fatty acid synthesis come from?
8. describe the recycling of oxaloacetate back to pyruvate in the cytosol.
9. acetyl coa synthesis in the mitochondria is stimulated by...
10. why doesn't citrate just get used in the TCA cycle after being synthesized in the mitochondria?
fatty acid synthesis...
11. describe the synthesis of malonyl CoA.
12. what is the rate limiting enzyme of fatty acid synthesis?
13. what is acetyl coA carboxylase regulated by?
14. describe the first steps of fatty acid synthesis on the fatty acid synthase enzyme.
15. describe how the fatty acid chain is elongated.
16. at what point is the fatty acid released from fatty acid synthase?
17. where does the elongation of palmitate occur?
18. what is the main difference between the processes of fatty acid synthesis and fatty acid elongation?
19. what is the main elongation reaction that occurs in the body?
desaturation...
20. what does desaturation of fatty acids require?
21. what are the most common desaturation reactions that take place in the body?
22. what is the limitation in the body's ability to unsaturate fatty acids?
23. where do we obtain w6 and w3 fatty acids?
24. what are linoleic and alpha-linolenic converted to in the body?
25. where do the w3 and w6 fatty acids in fish oil come from?
packaging...
26. where does G3P come from in the liver?
27. where does G3P come from in adipose tissue?
28. describe the synthesis of a triacylglycerol.
29. what is glyceroneogenesis? where and when does it occur? what is it regulated by?
30. what is a VLDL?
31. what is the major apoprotein in VLDL's?
32. how do VLDL's differ from chylomicrons?
33. how do VLDL's become mature?
fate...
34. what is the fate of VLDL's?
35. what is LPL activated by?
36. describe the difference in Km of LPL between muscle and adipose tissue.
37. what happens to the VLDL after the TG's have been removed?
38. describe what happens to fatty acids in adipose tissue in the fed state.
39. what happens to glycerol in the adipose tissue?
40. describe what happens to TG's in adipose tissue in the fasting state.
answers
1. whenever an excess of calories is consumed.
2. mostly in the liver, also in the adipose tissue.
3. in the cytosol
4. conversion to oxaloacetate via pyruvate carboxylase or acetyl coA via pyruvate dehydrogenase.
5. pyruvate in the mitochondria is converted to acetyl coA and combined with oxaloacetate to form citrate. citrate is shuttled out into the cytosol to and split back into oxaloacetate and acetyl coA via citrate lyase.
6. because pyruvate dehydrogenase is only found in the mitochondria, and acetyl coA can not directly cross the mitochondrial membrane.
7. from the pentose phosphate pathway and also from the recycling of oxaloacetate back to pyruvate in the cytosol.
8. oxaloacetate is reduced by malate dehydrogenase into malate. malate is oxidatively decarboxylated into pyruvate via malic enyzme. NADPH is formed in the second step.
9. a high insulin/glucagon ratio.
10. because of allosteric inhibition of isocitrate dehydrogenase.
11. acetyl CoA is oxidatively decarboxylated to malonyl CoA via acetyl CoA carboxylase.
12. acetyl CoA carboxylase.
13. acetyl CoA carboxylase is active in the dephosphorylated form; when insulin levels are high, it is dephosphorylated by a phosphatase. when energy supplies are low, an AMP-dependent protein kinase phosphorylates it back into the inactive form. also, malonyl CoA and palmitoyl CoA (an intermediate and a product of fatty acid synthesis) inhibit while acetyl CoA and citrate (reactants) stimulate the enzyme.
14. an acetyl CoA moiety is transferred to the cysteine-sulfhydryl group, then transferred to the sulfhydryl group. malonyl coA attaches to the sulfhydryl group and then undergoes a condensation reaction with the acetyl, forming a 4 carbon keto-acyl chain and releasing CO2.
15. the carboxyl at the omega end of the four carbon keto-acyl chain is then reduced to an alcohol, has water removed to form a double bond, and reduced again to form a single bond. the keto-acyl chain is then transferred to the cysteine-sulfhydryl group and malonyl is added to it in the same fashion as the first step.
16. when the fatty acid is 16 carbons long (palmitate), it is released via hydrolysis.
17. in the endoplasmic reticulum.
18. in fatty acid elongation, the fatty acyl attaches to a CoA on the fatty acid synthase complex, as opposed to a phosphopantetheinyl group.
19. elongation of palmitate (C16) to stearate (C18).
20. molecular oxygen, NADH, and cytochrome b5.
21. introduction of a double bond in position ∆9 as in the conversion of palmitic acid to palmitoleic acid and stearic acid to oleic acid.
22. the body can only introduce a double bond up to carbon ∆9. thus it can not produce omega-3 or 6 unsaturated fatty acids, which involve carbons beyond that point.
23. mainly from dietary plant oils: linoleic acid (18:2, ∆9,12), alpha-linolenic acid (18:3, ∆9,12,15)
24. arachidonic acid, eicosapentaenoic acid, precursors for eicosanoids.
25. the phytoplankton that they consume.
26. phosphorylation of glycerol via glycerol kinase, or from reduction of DHAP from glycolysis.
27. only from glucose via reduction of DHAP (there is no glycerol kinase enzyme in adipose)
28. two fatty acids combine with the glycerol 3-P to form phosphatidic acid, which is then phosphorylated to form diacylglycerol. a third fatty acid is added to diacylglycerol to form a triacylglycerol.
29. glyceroneogenesis is the formation of new glycerol molecules from gluconeogenic precursors such as alanine, aspartate, and malate. it occurs in the adipose tissue during the fasting state and is regulated by the presence of PEPCK enzyme.
30. a very low density lipoprotein particle which is packaged in the golgi apparatus, contains TG's, cholesterol, phospholipids, proteins, and released by the liver into circulation.
31. apoB-100, related to the apoB-48 in chylomicrons.
32. they are more dense because they contain a smaller proportion of TG's.
33. upon acquisition of apoproteins CII and E from HDL particles in circulation.
34. the TG's in the VLDL's get cleaved by lipoprotein lipase present in the endothelium basement membrane.
35. the C-II apoprotein.
36. muscle tissue LPL has a low Km, allowing muscle to use fatty acids even with concentration of VLDL's are low. adipose tissue LPL has a high Km and is most active in the fed state, when the concentration of circulating fatty acids is high.
37. they form intermediate-density lipoproteins or low density lipoproteins.
38. during the fed state, high insulin levels stimulate synthesis of LPL in adipose tissue capillaries, which releases fatty acids from VLDL's (and chylomicrons). fatty acids are activated and form triacylglycerols using the same pathway as in the liver.
39. since adipose tissue has no glycerol kinase, it can't use glycerol to produce more TG's. thus glycerol travels back into circulation to the liver.
40. glucagon activates a hormone sensitive lipase, which cleaves fatty acids off of TG's, which are released into the bloodstream along with glycerol.
real questions
where do fatty acid elongation and desaturation occur in the body?
why can't double bonds be produced beyond carbon 9 during unsaturation of fatty acids?
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