this unit reviewed some basic concepts about fat digestion and went into some more depth about the anatomy and physiology of the liver and gall bladder. the liver is located in the upper right quadrant of the abdomen, deep to the 5-10th ribs. it is suspended by the lesser omentum ligament, which attaches it to the intestine and the stomach, and the falciform ligament, which attaches it to the anterior of the abdominal wall. it has four lobes- left, right, quadrate, and caudate. the ligamentum teres (round ligament) is the vestigial remains of the umbilical vein that brought blood from the placenta. finally, the porta hepatis is the "hilum" or root of the liver (similar to the hilum of the lung) and contains the bile duct, hepatic portal vein and hepatic artery.
the liver receives nutrient rich and oxygen poor blood from the GI tract- specifically the gastric, splenic, and mesenteric arteries, which comes into the liver via the hepatic portal vein. it receives nutrient poor, oxygenated blood from the hepatic artery which branches off of the celiac artery. the liver cells, hepatocytes, are in hexagonal arrangements which have portal "triads" in each corner which contain bile ducts, hepatic portal veins, and hepatic arteries. in the center of the hexagons is the central vein, which leads to the hepatic vein, which leads to the inferior vena cava back to the heart. running from the edges of the hexagonal "lobule" are the sinuosoids where most of the functional activity of the liver takes place. the liver acinus theory describes the functional unit of the liver as the triangle between two portal triad corners and a central vein-- which is divided into three zones: zone 1 is closest to the central vein and although has lowest oxygen / nutrient content, is the site of most detoxification and chemical activity.
portal hypertension can occur from blockages in liver blood flow, resulting in a backpressure in portal circulation. this can cause a number of pathologies such as caput medusa, esophageal varicosities, and hemorrhoids. additionally, excess lymph can be drained from the liver (lymph drains into the space of disse, the tiny canals between the hepatocytes and sinusoids) and can collect in the peritoneal cavity, resulting in ascites. in this condition, the loss of fluid in the circulatory system must be compensated by renal devices which increase fluid retention such as aldosterone and renin secretion.
bile is secreted by hepatocytes and flows to the periphery of the hexogonal lobule, draining into the bile ducts, which drain into the right and left hepatic ducts. these combine to form the common hepatic duct, which combines with the bile duct from the gall bladder, called the cystic duct, to form the common bile duct. the common bile duct intersects with the main pancreatic duct at the hepatopancreatic ampulla and exits into the duodenum at the major duodenal papilla. the tissue around this point forms a sphincter called the sphincter of odie which contracts between meals or during fasting, which causes bile to stored in the gall bladder instead of being released into the duodenum.
bile stored in the gall bladder is made of bile salts, cholesterol, phospholipids, water, and can be concentrated over time via water reabsorption, or secretion of bile salts and cholesterol. if the bile becomes too concentrated in the gall bladder, over long periods of time with no contraction, then gall stones can precipitate out. in normal function, CCK and secretin are released from duodenal I and S cells, respectively, in response to protein, fat, or acid in the intestine (see "intestinal phase" in last lecture), causing an increase in pancreatic secretion, decrease in gastric secretion/motility, and bile release from gall bladder via contraction of the gall bladder and relaxation of the sphincter of odie. vagal stimulation can have the same effect. once in the intestine, bile surrounds fat molecules and aids in their absorption. the chapter in biochem covers this in much greater detail than what was presented in this lecture.
questions
location and anatomy...
1. where is the liver located?
2. what are the two ligaments that suspend the liver and where are they?
3. what are the lobes of the liver?
4. what is the ligamentum teres of the liver?
5. what is the porta hepatis?
physiology...
6. what are some of the functions of the liver?
7. how much blood does the liver receive (in terms of percentage of cardiac output)?
8. how does the liver get its oxygenated blood?
9. what does the portal vein bring to the liver? where does it bring it from?
10. what are sinusoids lined with?
11. what do the hepatic veins do?
lobules...
12. what is the classical lobule model of the liver?
13. what are the portal triads and what do they contain?
14. what is in the middle of the classical lobule?
15. what is the liver acinus model of the liver?
16. what are the three zones in the liver acinus model?
17. which zone is most susceptible to hypoxia and toxic damage?
hypertension and other pathologies...
18. where are the spaces of disse? what flows in them?
19. what is meant by "portal hypertension"?
20. what are some pathologies that portal hypertension can contribute to?
21. what is ascites?
22. how does ascites affect blood pressure?
bile secretion...
23. describe bile secretion by hepatocytes.
24. what are bile secretions made of?
25. what do the right and left hepatic ducts do?
26. ...common hepatic duct?
27. ...cystic duct
28. ...common bile duct
29. ...hepatopancreatic ampulla
30. ...main pancreatic duct
31. ...major duodenal papilla
gall bladder...
32. what are the three parts to the gall bladder?
33. what are three functions of the gall bladder?
34. how does the sphincter of oddi help store bile in the gall bladder?
35. describe two ways in which bile can be released by the gall bladder.
36. besides gall bladder emptying, what else does CCK mediate?
37. what effect does secretin have on the gall bladder and pancreas?
38. how are gallstones created?
39. what are two functions of bile?
micelles...
40. what is the general scheme for fat digestion?
41. about how big are micelles?
42. what pH is optimal for the action of pancreatic lipase?
43. which enzyme hydrolyzes cholesterol?
44. what are micelles made of?
45. how are bile salts formed?
46. what happens to the micelle contents at the enterocyte?
47. where does most of the reabsorption of bile acids and salts occur in the intestine?
chylomicrons and lipoproteins...
48. what are chylomicrons composed of?
49. 80-90% of chylomicrons are transported into...
50. how is the processing of short and medium chain fatty acids different?
51. what are the roles of: chylomicrons, VLDL, LDL, and HDL?
52. what makes feces brown and urine yellow?
53. jaundice is caused by...
answers
1. upper right abdomen between ribs 5-10.
2. lesser omentum between liver and stomach/intestine, falciform ligament between liver and anterior abdominal wall.
3. left, right, quadrate, caudate.
4. the round ligament, which is a vestigal remains of the umbilical vein carrying blood from the placenta to the fetus.
5. the "hilum" of the liver that contains bile ducts, hepatic arteries, and portal vein.
6. glycogen storage, gluconeogenesis, synthesis of TG's, cholesterol, phospholipids, fatty acid oxidation, protein synthesis, urea cycle, storage of vitamins and iron, detoxification, bile secretion.
7. 29%
8. via the celiac artery which branches off of the aorta
9. nutrient filled, deoxygenated blood from the gastric, splenic, and mesenteric veins.
10. hepatocytes
11. bring blood out of the superior aspect of the liver into the inferior vena cava.
12. divides hepatocytes into hexagonal "lobule" arrangements.
13. the corners of the hexagon in the classical lobule which contain the bile duct, hepatic artery and portal vein.
14. the central vein, which leads to the hepatic vein.
15. a model which has a functional "acinus" unit which is the triangle between two portal triads and a central vein.
16. zone 1 is closest to the portal triads and has the highest concentration of oxygen and nutrients. zone 2 is in the middle, zone 3 is closest to central vein and receives least nutrients but is primary site of alcohol and drug detoxification.
17. zone 3.
18. between hepatocytes and endothelium of sinusoids. lymph flows from sinusoids into space of disse, and sent to thoracic duct or inferior vena cava.
19. when a blockage of blood flow in the liver leads to backpressure in the portal circulation.
20. hemorrhoids, caput medusae, esophageal varicosities.
21. when portal hypertension causes excess lymph to flow in the space of disse, causing buildup of fluid in the peritoneal cavity.
22. since blood volume is lost to the lymph fluid that is trapped in the peritoneal cavity, blood pressure drops and the kidneys compensate by increasing salt and fluid retention until pressure is restored.
23. bile is secreted by hepatocytes and flows to the periphery of the portal lobules.
24. bile acids, phospholipids, cholesterol, along with bicarbonate and bile pigments (bilirubin)
25. bile outflow from the liver
26. junction between right and left hepatic ducts.
27. outflow from gall bladder.
28. outflow of bile from both gall bladder and liver.
29. junction of bile and pancreatic ducts.
30. outflow from pancreas.
31. bile and pancreatic secretion into duodenum.
32. body, neck, fundus.
33. store bile, concentrate bile, release bile into duodenum.
34. by contracting between meals, it allows backflow of bile from common bile duct into cystic duct into gall bladder.
35. CCK release triggered by fat or protein reach chyme entering the duodenum causes the sphincter of oddi to relax and the gall bladder to contract. vagus nerve stimulation has the same effect.
36. inhibits gastric mixing and secretion, stimulates intestinal mixing, stimulates pancreatic secretion.
37. increased water and bicarbonate secretion from duct cells.
38. either too much absorption of water (can be due to inflammation of epithelium), or high cholesterol content in stored bile (from too much absorption of bile salts, or too much secretion of cholesterol into bile)
39. to aid in fat digestion, and also elimination of various endogenous and exogenous substances such as cholesterol, bilirubin, drugs, heavy metals.
40. pancreatic lipase hydrolyzes triacylglycerides into free fatty acids, which are packaged into micelles via bile droplets. fatty acids are absorbed into enterocytes and bile is reabsorbed. fatty acids are reconverted to triacylglycerides, packaged into chylomicrons and transported in the blood.
41. ~1um
42. pH 8.
43. cholesterol esterase.
44. bile acids, phospholipids, cholesterol, and the fat that is trapped in the lipophilic core
45. bile acids are conjugated in the liver to form bile salts.
46. fatty acids are repackaged into triacylglycerol and cholesterol is esterified in the enterocyte, then packaged into a chylomicron in the ER.
47. the ileum.
48. cholesterol and triglycerides in a phospholipid shell with apoproteins.
49. lacteals and thoracic duct.
50. they are not packaged into chylomicrons and instead are transported directly into the venous system and stored in the liver and adipose.
51. chylomicrons transport fat from intestine into the blood. VLDL's transport triacylglycerides from the liver into the blood. LDL's are produced in plasma and trasnport cholesterol esters from liver to organs and tissues. HDL's are produced in plasma and transport cholesterol from peripheral tissues to the liver.
52. bilirubin is converted by colonic bacteria into urobilinogen, which can be excreted in the urine or converted to stercobilin and excreted in feces.
53. excess bilirubin
Showing posts with label lipids. Show all posts
Showing posts with label lipids. Show all posts
Thursday, March 5, 2009
Thursday, January 22, 2009
biochem: mark's medical biochem chapter 33- fatty acid synthesis
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?
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?
Monday, December 22, 2008
biochem: mark's medical biochem chapter 32- lipid digestion
this chapter traces the triacylglycerol molecule, the most common form of dietary lipid, from its ingestion to its eventual metabolism in skeletal muscle or adipose cells. triacylglycerol molecules are composed of a 3 carbon glycerol backbone and 3 fatty acids of varying chain lengths esterified to each carbon. digestion of lipids begins in the mouth and stomach, with secretions of lingual and gastric lipase, respectively. these enzymes hydrolyze the shorter chain fatty acids off of the triacylglycerol molecule, and are thus more active in children and infants who drink greater amounts of cow's milk, which contains triacylglycerol molecules with a higher proportion of short chain amino acids.
the main digestion of lipids begins in the intestines. when the stomach's acidic contents are dumped into the intestines, the enzyme cholecystokinin is secreted and stimulates the release of bile salts from the gall bladder. bile salts, in cooperation with the peristaltic action of the intestines, emulsify and breakdown the dietary lipids into smaller droplets, increasing the surface area to which pancreatic lipase has access to. pancreatic lipase is the main digestive enzyme for lipids and its net effect on a triacylglycerol molecule is to break it down into two free fatty acid molecules and a 2-monoacylglycerol molecule. these breakdown products are repackaged in bile salt "micelles", which then travel to the intestinal epithelium and are absorbed into the microvilli.
at this point the bile salts remain in the intestinal lumen (eventually to be reabsorbed in the ileum, transported to the liver, and stored back in the gall bladder), but the contents of the micelles are absorbed into the intestinal "enterocyte" cell. the previously disassembled fatty acids and 2-monoacylglycerol molecule are reassembled in the smooth ER of the enterocyte, and packaged into another protein chamber, called a "chylomicron", before leaving the enterocyte cell. the chylomicron, one of several types of "lipoproteins", basically serves as a small, hydrophilic container for the hydrophobic triacylglyceride molecules, and is outfitted with apoproteins which are involved in cell signaling downstream.
when chylomicrons are released from the enterocytes, they receive more apoproteins (E and CII) from yet another lipoprotein, HDL, and become "mature" chylomicrons. these two apoproteins allow the lipids to be metabolized in muscle or adipose cells- apoprotein E allows uptake of the chylomicron into cells, and apoprotein CII stimulates LPL, an enzyme which metabolizes the chylomicron's contents within the cell.
questions
1. what is the structure of a triacylglycerol?
2. why are gastric and lingual lipase more active in children and infants?
3. describe the action of bile salts on lipids.
4. what are bile salts stimulated by?
5. what is the major enzyme that digests triacylglycerols?
6. pancreatic lipase is secreted along with...
7. what is the function of bicarbonate?
8. bicarbonate secretion is stimulated by...
9. what does colipase do?
10. describe the effect of pancreatic lipase on triacylglycerols.
11. what happens to the fatty acids and monoacylglycerol that is produced from pancreatic lipase?
12. describe the life of a micelle.
13. what parts of a micelle get absorbed into the intestinal lining?
14. describe the fate of bile salts after being used in the intestine.
15. how does the absorption of short chain fatty acids differ from that of medium and long chain?
16. what happens to fatty acids in the endoplasmic reticulum of intestinal cells?
17. what are chylomicrons and why are they necessary in lipid digestion?
18. where are fatty acids resynthesized within intestinal epithelium cells? where are apoproteins synthesized?
19. what happens to chylomicrons after they are released from intestinal epithelial cells?
20. what distinguishes a "nascent" chylomicron from a "mature" one?
21. what is LPL?
22. describe the effect of insulin on LPL?
23. how does the Km for LPL compare in muscle and adipose cells? what is the implication?
24. what is the fate of the portions of chylomicrons that remain after digestion by LPL?
answers
1. a glycerol moiety with three fatty acids esterified to each carbon.
2. because they preferentially metabolize lipids with short chain fatty acids, which are consumed in large quantities by children in the form of cow's milk.
3. bile salts act as a "detergent" and bind to fat globules, increasing the surface area and thus the efficiency of metabolism by pancreatic enzymes.
4. cholecystokinin, secreted by intestinal cells when stomach contents enter the intestines.
5. pancreatic lipase.
6. colipase and bicarbonate.
7. bicarbonate neutralizes gastric acidity, raising pH to ~6.
8. secretin, which is secreted when acid enters the duodenum.
9. binds to dietary fats as well as lipase, increasing lipase activity.
10. pancreatic lipase hydrolyzes the fatty acids at positions 1 and 3 (of any chain length), resulting in 2 free fatty acids and 2-monoacylglycerol.
11. they are bound into micelles, tiny microdroplets which are emulsified by bile salts.
12. after formation, micelles travel through the "unstirred water layer" and then are absorbed into the microvilli of the intestinal lining.
13. fatty acids, monoacylglycerol, other dietary lipids are absorbed, but bile salts remain in the lumen.
14. 95% of bile salts are resorbed in the ileum, where they are transported via entero-hepatic circulation back to the liver, which stores the bile in the gall bladder for the next digestive cycle.
15. short chain fatty acids can be absorbed directly onto the intestinal lining without any packaging, and are transported to the liver via portal circulation (rather than lymph) bound to serum albumin.
16. fatty acids and monoacyl glycerides are re-synthesized into triacylglycerides and packaged into chylomicrons.
17. chylomicrons are small protein packages that contain triacylglycerides, proteins, and phospholipids. they are necessary because lipids are not water soluble and would therefore coalesce and block blood flow.
18. smooth ER, rough ER
19. they are transported via the "chyle" in the lymphatic system and enter the blood through the thoracic duct.
20. a nascent chylomicron is one that is recently secreted by the intestinal epithelial cells. a mature chylomicron is a lipoprotein that has had additional apoproteins transferred to it via HDL, such as apoprotein E and CII.
21. an enzyme on capillary endothelial cells that digests the triacylglycerol molecules within the chylomicrons.
22. insulin upregulates production of LPL so that after a mealtime, when triacylglyceride levels are high, fatty acids will be hydrolyzed.
23. the Km is lower in muscle cells, implying that muscle cells can more easily metabolize fatty acids, even when the concentration is low.
24. degradation and recycling by hepatocytes.
the main digestion of lipids begins in the intestines. when the stomach's acidic contents are dumped into the intestines, the enzyme cholecystokinin is secreted and stimulates the release of bile salts from the gall bladder. bile salts, in cooperation with the peristaltic action of the intestines, emulsify and breakdown the dietary lipids into smaller droplets, increasing the surface area to which pancreatic lipase has access to. pancreatic lipase is the main digestive enzyme for lipids and its net effect on a triacylglycerol molecule is to break it down into two free fatty acid molecules and a 2-monoacylglycerol molecule. these breakdown products are repackaged in bile salt "micelles", which then travel to the intestinal epithelium and are absorbed into the microvilli.
at this point the bile salts remain in the intestinal lumen (eventually to be reabsorbed in the ileum, transported to the liver, and stored back in the gall bladder), but the contents of the micelles are absorbed into the intestinal "enterocyte" cell. the previously disassembled fatty acids and 2-monoacylglycerol molecule are reassembled in the smooth ER of the enterocyte, and packaged into another protein chamber, called a "chylomicron", before leaving the enterocyte cell. the chylomicron, one of several types of "lipoproteins", basically serves as a small, hydrophilic container for the hydrophobic triacylglyceride molecules, and is outfitted with apoproteins which are involved in cell signaling downstream.
when chylomicrons are released from the enterocytes, they receive more apoproteins (E and CII) from yet another lipoprotein, HDL, and become "mature" chylomicrons. these two apoproteins allow the lipids to be metabolized in muscle or adipose cells- apoprotein E allows uptake of the chylomicron into cells, and apoprotein CII stimulates LPL, an enzyme which metabolizes the chylomicron's contents within the cell.
questions
1. what is the structure of a triacylglycerol?
2. why are gastric and lingual lipase more active in children and infants?
3. describe the action of bile salts on lipids.
4. what are bile salts stimulated by?
5. what is the major enzyme that digests triacylglycerols?
6. pancreatic lipase is secreted along with...
7. what is the function of bicarbonate?
8. bicarbonate secretion is stimulated by...
9. what does colipase do?
10. describe the effect of pancreatic lipase on triacylglycerols.
11. what happens to the fatty acids and monoacylglycerol that is produced from pancreatic lipase?
12. describe the life of a micelle.
13. what parts of a micelle get absorbed into the intestinal lining?
14. describe the fate of bile salts after being used in the intestine.
15. how does the absorption of short chain fatty acids differ from that of medium and long chain?
16. what happens to fatty acids in the endoplasmic reticulum of intestinal cells?
17. what are chylomicrons and why are they necessary in lipid digestion?
18. where are fatty acids resynthesized within intestinal epithelium cells? where are apoproteins synthesized?
19. what happens to chylomicrons after they are released from intestinal epithelial cells?
20. what distinguishes a "nascent" chylomicron from a "mature" one?
21. what is LPL?
22. describe the effect of insulin on LPL?
23. how does the Km for LPL compare in muscle and adipose cells? what is the implication?
24. what is the fate of the portions of chylomicrons that remain after digestion by LPL?
answers
1. a glycerol moiety with three fatty acids esterified to each carbon.
2. because they preferentially metabolize lipids with short chain fatty acids, which are consumed in large quantities by children in the form of cow's milk.
3. bile salts act as a "detergent" and bind to fat globules, increasing the surface area and thus the efficiency of metabolism by pancreatic enzymes.
4. cholecystokinin, secreted by intestinal cells when stomach contents enter the intestines.
5. pancreatic lipase.
6. colipase and bicarbonate.
7. bicarbonate neutralizes gastric acidity, raising pH to ~6.
8. secretin, which is secreted when acid enters the duodenum.
9. binds to dietary fats as well as lipase, increasing lipase activity.
10. pancreatic lipase hydrolyzes the fatty acids at positions 1 and 3 (of any chain length), resulting in 2 free fatty acids and 2-monoacylglycerol.
11. they are bound into micelles, tiny microdroplets which are emulsified by bile salts.
12. after formation, micelles travel through the "unstirred water layer" and then are absorbed into the microvilli of the intestinal lining.
13. fatty acids, monoacylglycerol, other dietary lipids are absorbed, but bile salts remain in the lumen.
14. 95% of bile salts are resorbed in the ileum, where they are transported via entero-hepatic circulation back to the liver, which stores the bile in the gall bladder for the next digestive cycle.
15. short chain fatty acids can be absorbed directly onto the intestinal lining without any packaging, and are transported to the liver via portal circulation (rather than lymph) bound to serum albumin.
16. fatty acids and monoacyl glycerides are re-synthesized into triacylglycerides and packaged into chylomicrons.
17. chylomicrons are small protein packages that contain triacylglycerides, proteins, and phospholipids. they are necessary because lipids are not water soluble and would therefore coalesce and block blood flow.
18. smooth ER, rough ER
19. they are transported via the "chyle" in the lymphatic system and enter the blood through the thoracic duct.
20. a nascent chylomicron is one that is recently secreted by the intestinal epithelial cells. a mature chylomicron is a lipoprotein that has had additional apoproteins transferred to it via HDL, such as apoprotein E and CII.
21. an enzyme on capillary endothelial cells that digests the triacylglycerol molecules within the chylomicrons.
22. insulin upregulates production of LPL so that after a mealtime, when triacylglyceride levels are high, fatty acids will be hydrolyzed.
23. the Km is lower in muscle cells, implying that muscle cells can more easily metabolize fatty acids, even when the concentration is low.
24. degradation and recycling by hepatocytes.
Subscribe to:
Posts (Atom)