here is the section in the GI notes on liver diagnosis that i missed when we were in the thick of the semester...
liver dysfunction can manifest in many different body systems: liver failure or cirrhosis might cause generalized fatigue / anorexia / weight loss. an infection or inflammation of the liver might cause a fever. bad breath might result from abnormal methionine metabolism in late cirrhosis. bilirubin backup can appear as jaundice, or even pruritis. increased serum lipids might lead to xanthomas and xanthelasmas. improper estrogen / androgen metabolism might result in gynecomastia and testicular atrophy, as well as spider telangiectasias.
fatty liver is a fairly common dysfunction of the liver that afflicts about 25-30% of the population. it results from abnormal accumulation of fat droplets within the liver, which can ultimately lead to fibrosis, scarring, and cirrhosis. it is not directly caused by fatty food intake- other risk factors include diabetes and alcoholism. clinically, it might present as liver enlargement and slight elevation of liver enzymes. if steatosis progresses to fibrosis (and if alcohol is not involved), then non alcoholic steatohepatitis develops. this is more likely to occur in middle aged, obese, diabetic women who are on hormone therapy such as synthetic estrogen. like simple fatty liver, it might present simply as an enlarged liver and slightly elevated liver enzymes with no other symptoms, or might present with increased BP, palmar erythema, muscle aches/fatigue, muddy sclera.
hepatitis is inflammation and necrosis of the liver and infectious hepatitis can occur in several different flavors, hep A through E mostly. these all present with similar symptoms, including flu like symptoms, jaundice, RUQ pain, and have similar stages of development which include a prodromal phase with generalized symptoms. each variant has a particular mode of transmission: A and E are mostly via fecal oral, or oral/anal sexual practices. B and D are via unprotected sex or contaminated syringes, and C is mainly from contaminated syringes. all forms might present with an enlarged, tender liver and may have splenomegaly as well. labs that might aid in diagnosis: high ALT / AST, bilirubin, low albumin / platelets, normal WBC.
prolonged acute hepatitis can result in chronic inflammation which might lead to chronic hepatitis, which can come in several varities: lobular, persistent, and active (most likely to lead to failure/cirrhosis). presentation can be similar to acute, or nonspecific, or lupoid like symptoms. lab findings might be similar, with high ALT / AST, bilirubin, prolonged PT, decreased albumin, hyperglobulinemia, and presence of ANA in lupoid presenting patients. diagnosis is by liver biopsy and differential should consider wilson's disease if serum copper is elevated.
fulminant hepatic failure is defined as a combination of acute liver failure and encephalopathy that develops in less than 8 months with no prior history of liver dysfunction. it can be caused by a number of factors such as viruses, fatty liver, ischemia, toxin buildup. it might develop into coma, hypoglycemia, cerebral or GI hemorrhage, renal insufficiency-- despite this, the long term prognosis is excellent.
cirrhosis of the liver occurs after longstanding injury or inflammation of the liver from a variety of causes and is a combination of fibrosis, necrosis, regeneration, ultimately resulting in hepatocyte shrinking. it is most commonly caused by hep C, then alcoholism, then hep B and cryptogenic causes. if it is due to alcohol, the liver might feel both enlarged and with a bumpy edge. cirrhosis can present with clubbing, dupuytren's contracture, fetor hepaticus, pleural effusion, and dilated abdominal veins. additionally, because of restricted blood flow, it results in portal hypertension and can cause ascites and esophageal varices.
cirrhosis predisposes to formation of liver cancer, hepatocellular carcinoma. HCC can also be related to chronic alcoholism, childhood hep B infection, hep C (especially in japan and europe), HBV, hemocromatosis. prognosis is not good; usually leads to death within 6-20 months. it presents similarly to advanced cirrhosis and lab markers such as transaminases, alk phos, bilirubin, LDH are elevated. alpha fetal protein is elevated in 75% of cases and is a good way to predict for HCC.
liver tumors can also be benign, as in the case of hepatic adenoma- which is most commonly seen in women in their 30's on birth control pills. they would present asymptomatically, or with hepatomegaly if the tumor was big enough, or with RUQ pain if ruptured (rare). once oral contraceptives are stopped, prognosis is good.
finally, gilbert's syndrome is an autosomal recessive disorder in which bile pigment clearance from the liver is impaired, resulting in elevated bilirubin levels without outright liver damage. it might be triggered by dehydration, stress, menses, viruses, fasting, and might only present with mild jaundice and vague symptoms like abdominal cramping and fatigue. diagnosis is by excluding hemolysis by testing for normal LDH and CBC reports, and liver tests to confirm that liver function is normal (except for unconjugated bilirubin).
questions
how might the following symptoms be related to liver dysfunction?
1. fatigue / anorexia / malaise / weight loss.
2. fever.
3. fetor hepaticus.
4. spider telangiectasias.
5. jaundice.
6. pruritis.
7. xanthoma / xanthelasma.
8. gynecomastia / testicular atrophy.
9. hypoglycemia.
10. abdominal swelling.
11. behavioral changes.
fatty liver...
12. what are the top 3 causes of chronic liver disease?
13. what percentage of the population does fatty liver affect?
14. describe the general progression of pathogenesis from fatty liver to cirrhosis.
15. what are some etiological factors for fatty liver?
16. what are some diagnostic signs for fatty liver?
NASH...
17. how big a factor does NASH play in chronic liver disease?
18. what is the etiology of NASH?
19. describe the patient type that is at greatest risk for developing NASH.
20. many patients with NASH show an elevation of...
21. what is the clinical picture of a patient with NASH?
acute viral hepatitis...
22. what is hepatitis?
23. what are the four stages of presentation of infectious hepatitis?
24. what are the hallmarks of hep. A signs / symptoms?
25. when is the period of greatest infectivity in hep A and how long does it take for hep A to resolve?
26. what is the risk of complication for hep B and C?
27. Hep D requires...
28. where in the world is hep E most likely to be found?
29. how are hep A and E transmitted?
30. how are hep B and D transmitted?
31. how is hep C transmitted?
32. what are some PE signs for patients with infectious hepatitis?
33. what are some lab findings that can aid in the diagnosis of infectious hepatitis?
34. what are some potential complications of infectious hepatitis?
chronic hepatitis...
35. what is the etiology of chronic hepatitis?
36. what are three types of chronic hepatitis? which is the most serious?
37. what are the signs/symptoms of chronic hepatitis?
28. what are the lab findings expected to be found in chronic hepatitis?
29. if a patient has chronic hepatitis symptoms plus high serum copper, what should be considered as a DDX?
30. what is a way to differentiate between alcoholic and non alcoholic hepatitis by lab tests?
fulminant hepatic failure...
31. what is fulminant hepatic failure?
32. what are some etiologies for fulminant hepatic failure?
33. what are the signs/symptoms of fulminant hepatic failure?
34. what are the complications of fulminant hepatic failure?
35. what is the prognosis of fulminant hepatic failure?
cirrhosis...
36. what is cirrhosis?
37. what are the most common causes of hepatic cirrhosis?
38. what are the two presentations of a patient with hepatic cirrhosis?
39. what might the liver feel like for a patient with cirrhosis due to alcohol?
40. cirrhosis is the most common cause of...
41. why might cirrhosis have normal or low liver enzymes?
42. what markers might be elevated with liver cirrhosis?
43. what are some complications of cirrhosis?
44. what are two other potential causes of cirrhosis?
liver cancer...
45. HCC leads to death in...
46. what are some risk factors for HCC?
47. what is the median age of diagnosis of HCC in the US and europe?
48. how great of a risk factor for HCC is cirrhosis?
49. what percentage of HCC is related to alcohol use?
50. what is the most common cause of HCC in japan and europe?
51. what are the signs and symptoms for liver cancer?
52. what are some lab markers that would be increased in liver cancer?
53. which lab marker is elevated in 75% of HCC cases?
hepatic adenoma...
54. describe the patient type that is most likely to have a hepatic adenoma.
55. what are the signs and symptoms of hepatic adenoma?
56. what is the severity and prognosis of HA's?
57. what is a PE finding that hepatic adenoma might present with?
58. what is a ddx for HA and why?
gilbert's syndrome...
59. what is gilbert's syndrome?
60. how common is gilbert's syndrome?
61. what are the etiologies / triggers of gilbert's syndrome?
62. what is the clinical presentation of gilbert's syndrome patients?
63. what labs are performed to diagnose gilbert's and why?
answers
1. liver failure / cancer / cirrhosis.
2. infectious hepatitis or inflammation.
3. abnormal methionine metabolism; late stage of cirrhosis.
4. altered estrogen / androgen metabolism.
5. elevated bilirubin from decreased ability of liver to metabolize and excrete bilirubin.
6. elevated bilirubin levels again- skin is an elimination pathway.
7. increased serum lipids.
8. improper estrogen / androgen metabolism.
9. impaired gluconeogenesis.
10. ascites from portal hypertension.
11. hepatic encephalopathy.
12. hep C, alcohol, then hep B.
13. 25-30%.
14. fatty deposits in liver cause enlargement, leading to fibrosis and scarring, which eventually leads to cirrhosis.
15. diabetes, poor diet, heavy alcohol use.
16. enlarged liver, slightly elevated liver enzymes. confirmed by liver biopsy.
17. third most common reason for chronic liver failure after hep C and alcoholism.
18. no known specific cause.
19. middle aged, obese, diabetic woman taking hormones but doesn't drink alcohol.
20. ferritin.
21. asymptomatic, or
enlarged liver
palmar erythema
increased systolic BP
muddy sclera
muscle aches / fatigue
22. inflammation of the liver with patched or scattered necrosis affecting all acini.
23. viral replication (asymptomatic), prodrome (generalized symptoms), icteric (jaundice, darkened urine, RUQ pain), convalescence.
24. flu symptoms, abdominal cramps, jaundice.
25. 1-2 days before onset of jaundice, 2 months to resolve.
26. 10% of hep B and 80% of hep C patients can develop longstanding liver inflammation which might result in liver cirrhosis and failure.
27. hep B virus.
28. developing countries, rare in the US.
29. fecal/oral, contaminated food or water. high association with oral / anal sexual practices.
30. unprotected sex, contaminated syringes.
31. mostly contaminated syringes.
32. liver tender and enlarged, may see splenomegaly as well.
33. huge elevations of ALT / AST
hyperbilirubinemia
low platelets, albumin
normal WBC
34. post hepatitis syndrome, cholestatic hepatitis, fulminant hepatitis, chronic hepatitis.
35. all forms of infectious except for A and E.
36. persistent, lobular, active (most serious).
37. asymptomatic or
nonspecific
or present like acute hepatitis
hepatosplenomegaly
jaundice
lupoid symptoms
serious systemic illness symptoms: cutaneous, constitutional symptoms.
28. elevated AST, ALT, bilirubin, prolonged PT, decreased albumin, hyperglobulinemia, ANA.
29. wilson's disease.
30. strikingly high WBC count, and only moderate elevation of AST/ALT in alcoholic hepatitis.
31. liver failure and encephalopathy which develops in less than 8 weeks with no prior history of liver disease.
32. viral, fatty liver, ischemia, toxins.
33. symptoms of encephalopathy
symptoms of acute liver failure
ascites
hypoprothrombinemia
malnutrition.
34. cerebral hemorrhage
coma
hypoglycemia
Gi hemorrhage
renal insufficiency
35. 20% short term, excellent long term.
36. triad of parenchymal necrosis, fibrosis, regeneration from longstanding inflammation or injury.
37. hep C
alcoholism
hep B
"cryptogenic causes"
38. "well compensated"- asymptomatic
"decompensated":
clubbing
Dupuytren's contracture
fetor hepaticus
pleural effusion
dilated abdominal veins
[club dupuy fetor lungs stomach] [club deco- a contract for your feet, lungs, and stomach]
39. enlarged liver with bumpy, nodular edge.
40. ascites.
41. because of the shrinking and loss of functional hepatocytes.
42. bilirubin
transaminases
alk phos
PT
gamma globulin
43. GI hemorrhage
encephalopathy
renal failure
liver cancer
ascites
44. primary biliary cirrhosis, obstructive biliary cirrhosis.
45. 6-20 months.
46. asians, childhood hep B infection, cirrhosis, HBV, hemochromatosis.
47. 65 years old.
48. 80% of patients with HCC have preexisting cirrhosis.
49. 30%.
50. HCV.
51. present similar to advanced cirrhosis:
pruritis
jaundice
splenomegaly
varices
cachexia
ascites
[pj's vac]
52. transaminases
alk phos
bilirubin
LDH
AFP
[taable]
53. AFP.
54. 34 year old female who takes birth control pills.
55. asymptomatic.
56. benign and go away when OCP's halted.
57. RUQ mass or hepatomegaly.
58. cholecystitis because rupture can cause acute RUQ pain.
59. an autosomal recessive disorder that results in defective bile clearance from the liver which causes elevated bilirubin.
60. 3-5% population.
61. dehydration
stress
menstrual periods
viral infection
fasting
62. asymptomatic or nonspecific findings. may have mild jaundice.
63. CBC and LDH to rule out hemolysis, liver enzymes to rule out liver damage.
Showing posts with label liver. Show all posts
Showing posts with label liver. Show all posts
Sunday, March 21, 2010
Thursday, March 5, 2009
organ systems: the liver and lipid digestion
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
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
Monday, December 1, 2008
biochem: mark's medical biochemistry chapter 31- gluconeogenesis
gluconeogenesis is the process that occurs mainly in the liver in which glucose is produced from non-carbohydrate sources during times of fasting, exercise, or stress. it is essentially the opposite of glycolysis, in that instead of producing pyruvate from glucose, it synthesizes glucose from pyruvate. pyruvate itself is supplied by several different sources: lactate can be oxidized into pyruvate and is available from anaerobic glycolysis or by adipocytes in red blood cells. alanine can be transaminated into pyruvate and is produced from other amino acids released from the muscle. glycerol also serves as the precursor to an intermediate of gluconeogenesis, DHAP. the reactions of gluconeogenesis can be divided into three major sections:
conversion of pyruvate to phosphoenolpyruvate (PEP)
1. pyruvate is formed from alanine or lactate in the cytosol.
2. pyruvate diffuses into the mitochondria and is carboxylated to oxaloacetate via pyruvate carboxylase (recall that this is an anaplerotic reaction of the TCA cycle)
3. oxaloacetate is either transaminated to aspartate, or reduced to malate (using NADH as an electron source) and transported back out of the mitochondria.
4. oxaloacetate is reformed in the cytosol either by transamination of aspartate or oxidation of malate.
5. oxaloacetate is converted to phosphoenolpyruvate via phosphoenolpyruvate carboxykinase, using one GTP.
conversion of PEP to fructose 1,6 bisphosphate (reverse of glycolysis)
6. PEP is converted to 2-phosphoglycerate
7. 2-phosphoglycerate is converted to 3-phosphoglycerate
8. 3-phosphoglycerate is converted to 1,3-bisphosphoglycerate
9. 1,3-bisphosphoglycerate is converted to G3P.
10. for every two molecules of G3P that are formed, one isomerizes to DHAP
11. G3P condenses with DHAP to form fructose 1,6 bisphosphate.
conversion of fructose 1,6 bisphosphate to glucose (reverse of glycolysis)
12. fructose 1,6 bisphosphate is converted to fructose 6-phosphate via fructose 1,6 bisphosphatase.
13. fructose 6-phosphate is isomerized to glucose 6-phosphate via phosphoglucoisomerase.
14. glucose 6-phosphate is converted to glucose via glucose 6-phosphatase.
the reactions in bold are irreversible, endergonic reactions that use enzymes that are not used in the reverse glycolytic pathway. this is significant because the relative activity of these competing enzymes determines whether the reaction will proceed in the glycolytic or gluconeogenic pathway. the regulation of the first of these reactions, the conversion of oxaloacetate to PEP, is the most complex and is regulated by several enzymes in upstream reactions beginning with pyruvate production. the first, pyruvate dehydrogenase, is normally responsible for oxidizing pyruvate to acetyl CoA but is deactivated during gluconeogenesis, allowing pyruvate to instead be carboxylated into oxaloacetate. pyruvate carboxylase, the enzyme that catalyzes this reaction, is in turn activated by acetyl CoA, which is produced during the fatty acid oxidation which occurs during fasting or stress. these two reactions work in tandem during fasting conditions to ensure production of oxaloacetate from pyruvate rather than acetyl CoA.
the third enzyme which takes place in the regulation of the production of PEP is PEP carboxykinase, which converts oxaloacetate to PEP. in fasting conditions, glucagon and epinephrine stimulate cAMP to increase transcription of PEPCK enzymes, increasing the quantity of enzyme in the cell (called inducing). finally, the last enzyme involved is pyruvate kinase, which normally converts PEP back into pyruvate (recall the last step of glycolysis). high glucagon levels causes phosphorylation of the enzyme (using a mechanism involving cAMP and protein kinase A) and inactivates it-- thus allowing PEP to be used for gluconeogenesis instead of being uselessly cycled back to pyruvate. these four enzymes basically act as "switches" which first turn on the gluconeogenic pathway by allowing pyruvate to be converted to PEP.
the next places for enzymatic regulation of the gluconeogenic pathway are: the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, and the conversion of glucose 6-phosphate into glucose. both reactions are similar in that (as mentioned earlier) they use enzymes that are not the same as the reverse glycolytic reaction. in fasting conditions, the enzymes that catalyze the glycolytic reaction are deactivated, allowing the reaction to proceed in the gluconeogenic direction.
the book then talks about what happens in the liver and body tissues during, after, and long after a meal. during a high carbohydrate meal, blood glucose levels can rise from the normal 80-100 mg/dL to a high of 140 mg/dL. during this time insulin is secreted from the beta cells in the pancreas, and glucagon levels decrease. the net result is a storage of glucose in the liver as glycogen. within a few hours after eating, blood glucose and insulin levels fall back down, and glucagon levels start to rise- this initiates the process of glycogenolysis, which is the conversion of the stored glycogen in the liver back into glucose to maintain blood glucose levels. glucagon stimulates glycogenolysis and inhibits glycogen storage concurrently via production of cAMP, which stimulates protein kinase A to inactivate the enzyme related to glycogen synthesis as well as activate the glycogenolytic pathway. within 4 hours after a meal, as the liver's glycogen supply is decreasing (it takes about 30 hours to deplete the liver's supply of glycogen), gluconeogenesis is also stimulated by glucagon and falling blood sugar levels.
questions
1. what happens in the liver during fasting?
2. what is gluconeogenesis?
3. what are the three carbon sources for gluconeogenesis in humans?
4. describe the role of lactate as a gluconeogenic precursor.
5. describe the role of alanine as a gluconeogenic precursor.
6. describe the role of glycerol in gluconeogenesis.
7. describe the conversion of pyruvate to PEP.
8. what determines the path in which oxaloacetate will be converted and transported across the mitochondrial membrane?
9. describe the conversion of PEP to fructose 1,6 bisphosphate.
10. describe the conversion of fructose 1,6 bisphosphate to glucose.
11. describe the conversion of glycerol to DHAP.
12. what are other factors that can stimulate gluconeogenesis?
13. what are the three main reactions that are regulated in gluconeogenesis?
14. how does the fasting state deactivate pyruvate dehydrogenase?
15. how does the fasting state activate pyruvate carboxylase?
16. how is PEP carboxykinase regulated?
17. what is pyruvate kinase and how is it regulated?
18. describe the regulation of the reaction from fructose 1,6 bisphosphate to fructose 6-phosphate.
19. describe the regulation of the reaction from glucose 6-phosphate to glucose.
20. what is the energy consumption during gluconeogenesis and where does it happen?
21. what are normal blood glucose levels for fasting, right after a meal, 2 hours after a meal, and starvation?
22. describe the pancreas's actions after ingestion of a high glucose meal.
23. glycerol, glucagon, glycogen.
24. describe the stimulation of glycogenolysis in the liver.
25. describe what happens roughly 4 hours after a meal.
26. describe what happens during prolonged starvation.
27. how long does it take to deplete liver glycogen stores? (and therefore halt glycogenolysis)
answers
1. liver releases glucose into the blood via glycogenolysis and gluconeogenesis.
2. the process by which glucose is created in the liver from non carbohydrate sources.
3. lactate, glycerol, and amino acids- particularly alanine.
4. lactate is produced by anaerobic glycolysis through reduction of pyruvate or by adipocytes in the fed state or by red blood cells. lactate is oxidized into pyruvate, which is a precursor for gluconeogenesis.
5. alanine is produced in the muscle from other amino acids (whenever insulin is low or stress hormones are high) and from glucose. it is converted to pyruvate via alanine aminotransferase.
6. glycerol is released from adipose tissue whenever insulin levels are low or stress hormones are high. it is converted to DHAP, which is a gluconeogenetic intermediate (as well as a glycolytic one)
7. pyruvate is created from alanine or lactate in the cytosol, and then travels into the mitochondria, where it is carboxylated to oxaloacetate via pyruvate carboxylate (an anaplerotic reaction of the TCA cycle). oxaloacetate is then transaminated to aspartate or reduced to malate and transported back out into the cytosol, and reformed back into oxaloacetate (via oxidation or transamination). in the cytosol, oxaloacetate is decarboxylated by phosphoenolpyruvate carboxylkinase to form PEP.
8. the reduction of oxaloacetate into malate requires reducing equivalents; if the mitochondria has need for reducing equivalents for other reactions, it will use the other venue, the conversion to aspartate.
9. PEP is converted to fructose 1,6 bisphophate through a reversal of the glycolytic reactions. PEP is converted into 2-phosphoglycerate, to 3-phosphoglycerate, to 1,3 bisphosphoglycerate, and reduced to G3P. for every two molecules of G3P produced, one isomerizes to DHAP. G3P and DHAP condense to form fructose 1,6 bisphosphate.
10. fructose 1,6 bisphosphate has a phosphate removed by fructose 1,6bisphosphatase to form fructose 6 phosphate. fructose 6 phosphate is isomerized to glucose 6 phosphate by phosphoglucose isomerase. glucose 6 phosphate has a phosphate removed by glucose 6-phosphatase, producing glucose.
11. glycerol is converted to glycerol 3-phosphate via glycerol kinase, and then oxidized to DHAP.
12. prolonged exercise, stress, and a high protein diet.
13. OAA to PEP, fructose 1,6 bisphosphate to fructose 6 phosphate, glucose 6 phosphate to glucose. all three reactions use regulatory enzymes which are not involved in the reverse glycolytic pathway.
14. during the fasting state, fatty acids are released from adipose tissue and undergo beta oxidation, producing NADH, acetyl CoA, and ATP. the higher ATP / ADP ratio phosphorylates pyruvate dehydrogenase into the inactive form.
15. fatty acid oxidation produces acetyl CoA, which activates pyruvate carboxylase.
16. glucagon is released during fasting and EP is released during exercise/stress, both of which stimulate production of cAMP, which increases transcription of PEPCK genes.
17. pyruvate kinase is the enzyme that catalyzes the conversion of PEP back into pyruvate. when glucagon levels are high, pyruvate kinase is phosphorylated and inactive through a mechanism involving cAMP and protein kinase A.
18. this reaction occurs via the fructose 1,6 bisphosphotase enzyme, and normally would compete with the reverse reaction from glycolysis, fructose 6-phosphate to fructose 1,6 biphosphate via PFK-1. however, under conditions favoring gluconeogenesis, the enzymes that stimulate PFK-1 are inactive, allowing the reaction to head towards the production of glucose.
19. low insulin and glucose levels deactivate the enzyme for the glycolytic forward reaction and allow the glucose synthesis to occur.
20. for every mole of glucose that is produced, 6 moles of ATP and 2 moles of NADH are used. 2 moles of ATP at the conversion of pyruvate to oxaloacetate, 2 moles of ATP at the conversion of oxaloacetate to PEP, 2 moles of ATP at the conversion from 3-phosphoglycerate to 1,3 bisphosphoglycerate, and 2 moles of NADH at the reduction of 1,3 bisphospholycerate to G3P. (2 moles at each reaction because 2 molecules of pyruvate combine into one molecule of glucose)
21. fasting: 80-100mg/dL. right after a meal: up to 140mg/dL. 2 hours after a meal: back to 80-100mg/dL. starvation: not lower than 65mg/dL.
22. during a meal, the high glucose concentration in the blood stimulates the beta cells of the pancreas to increase insulin production. glucagon levels decrease in response to a high carbohydrate meal but increase in response to a high protein meal.
23. glycerol is released from adipose whenever levels of insulin are low and levels of glucagon is high-- and is converted into DHAP. glucagon is a hormone released by the alpha cells of the pancreas in response to decreasing blood glucose levels-- stimulating gluconeogenesis. glucagon also activates production of cAMP in liver cells, which activates protein kiase A, which inactivates glycogen synthase-- thus high glucagon levels inhibit glycogen production. glycogen is synthesized from glucose and stored in the liver.
24. high glucagon levels stimulate adenylate cyclate, which synthesizes cAMP. cAMP activates protein kinase A, which inactivates glycogen synthase, and activates phosphorylase kinase. phosphorylase activates phosphorylase b, which converts glycogen to glucose 1-P, which is then converted to glucose 6-P and then free glucose in the liver, which can then enter the blood.
25. in addition to supplementing blood glucose levels with glycogenolysis, gluconeogenesis is stimulated by the release of precursor material such as glycerol, alanine, and lactate from peripheral body tissues.
26. the body switches to fatty acid and ketone body oxidation and requires much less glucose.
27. ~30 hours
conversion of pyruvate to phosphoenolpyruvate (PEP)
1. pyruvate is formed from alanine or lactate in the cytosol.
2. pyruvate diffuses into the mitochondria and is carboxylated to oxaloacetate via pyruvate carboxylase (recall that this is an anaplerotic reaction of the TCA cycle)
3. oxaloacetate is either transaminated to aspartate, or reduced to malate (using NADH as an electron source) and transported back out of the mitochondria.
4. oxaloacetate is reformed in the cytosol either by transamination of aspartate or oxidation of malate.
5. oxaloacetate is converted to phosphoenolpyruvate via phosphoenolpyruvate carboxykinase, using one GTP.
conversion of PEP to fructose 1,6 bisphosphate (reverse of glycolysis)
6. PEP is converted to 2-phosphoglycerate
7. 2-phosphoglycerate is converted to 3-phosphoglycerate
8. 3-phosphoglycerate is converted to 1,3-bisphosphoglycerate
9. 1,3-bisphosphoglycerate is converted to G3P.
10. for every two molecules of G3P that are formed, one isomerizes to DHAP
11. G3P condenses with DHAP to form fructose 1,6 bisphosphate.
conversion of fructose 1,6 bisphosphate to glucose (reverse of glycolysis)
12. fructose 1,6 bisphosphate is converted to fructose 6-phosphate via fructose 1,6 bisphosphatase.
13. fructose 6-phosphate is isomerized to glucose 6-phosphate via phosphoglucoisomerase.
14. glucose 6-phosphate is converted to glucose via glucose 6-phosphatase.
the reactions in bold are irreversible, endergonic reactions that use enzymes that are not used in the reverse glycolytic pathway. this is significant because the relative activity of these competing enzymes determines whether the reaction will proceed in the glycolytic or gluconeogenic pathway. the regulation of the first of these reactions, the conversion of oxaloacetate to PEP, is the most complex and is regulated by several enzymes in upstream reactions beginning with pyruvate production. the first, pyruvate dehydrogenase, is normally responsible for oxidizing pyruvate to acetyl CoA but is deactivated during gluconeogenesis, allowing pyruvate to instead be carboxylated into oxaloacetate. pyruvate carboxylase, the enzyme that catalyzes this reaction, is in turn activated by acetyl CoA, which is produced during the fatty acid oxidation which occurs during fasting or stress. these two reactions work in tandem during fasting conditions to ensure production of oxaloacetate from pyruvate rather than acetyl CoA.
the third enzyme which takes place in the regulation of the production of PEP is PEP carboxykinase, which converts oxaloacetate to PEP. in fasting conditions, glucagon and epinephrine stimulate cAMP to increase transcription of PEPCK enzymes, increasing the quantity of enzyme in the cell (called inducing). finally, the last enzyme involved is pyruvate kinase, which normally converts PEP back into pyruvate (recall the last step of glycolysis). high glucagon levels causes phosphorylation of the enzyme (using a mechanism involving cAMP and protein kinase A) and inactivates it-- thus allowing PEP to be used for gluconeogenesis instead of being uselessly cycled back to pyruvate. these four enzymes basically act as "switches" which first turn on the gluconeogenic pathway by allowing pyruvate to be converted to PEP.
the next places for enzymatic regulation of the gluconeogenic pathway are: the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, and the conversion of glucose 6-phosphate into glucose. both reactions are similar in that (as mentioned earlier) they use enzymes that are not the same as the reverse glycolytic reaction. in fasting conditions, the enzymes that catalyze the glycolytic reaction are deactivated, allowing the reaction to proceed in the gluconeogenic direction.
the book then talks about what happens in the liver and body tissues during, after, and long after a meal. during a high carbohydrate meal, blood glucose levels can rise from the normal 80-100 mg/dL to a high of 140 mg/dL. during this time insulin is secreted from the beta cells in the pancreas, and glucagon levels decrease. the net result is a storage of glucose in the liver as glycogen. within a few hours after eating, blood glucose and insulin levels fall back down, and glucagon levels start to rise- this initiates the process of glycogenolysis, which is the conversion of the stored glycogen in the liver back into glucose to maintain blood glucose levels. glucagon stimulates glycogenolysis and inhibits glycogen storage concurrently via production of cAMP, which stimulates protein kinase A to inactivate the enzyme related to glycogen synthesis as well as activate the glycogenolytic pathway. within 4 hours after a meal, as the liver's glycogen supply is decreasing (it takes about 30 hours to deplete the liver's supply of glycogen), gluconeogenesis is also stimulated by glucagon and falling blood sugar levels.
questions
1. what happens in the liver during fasting?
2. what is gluconeogenesis?
3. what are the three carbon sources for gluconeogenesis in humans?
4. describe the role of lactate as a gluconeogenic precursor.
5. describe the role of alanine as a gluconeogenic precursor.
6. describe the role of glycerol in gluconeogenesis.
7. describe the conversion of pyruvate to PEP.
8. what determines the path in which oxaloacetate will be converted and transported across the mitochondrial membrane?
9. describe the conversion of PEP to fructose 1,6 bisphosphate.
10. describe the conversion of fructose 1,6 bisphosphate to glucose.
11. describe the conversion of glycerol to DHAP.
12. what are other factors that can stimulate gluconeogenesis?
13. what are the three main reactions that are regulated in gluconeogenesis?
14. how does the fasting state deactivate pyruvate dehydrogenase?
15. how does the fasting state activate pyruvate carboxylase?
16. how is PEP carboxykinase regulated?
17. what is pyruvate kinase and how is it regulated?
18. describe the regulation of the reaction from fructose 1,6 bisphosphate to fructose 6-phosphate.
19. describe the regulation of the reaction from glucose 6-phosphate to glucose.
20. what is the energy consumption during gluconeogenesis and where does it happen?
21. what are normal blood glucose levels for fasting, right after a meal, 2 hours after a meal, and starvation?
22. describe the pancreas's actions after ingestion of a high glucose meal.
23. glycerol, glucagon, glycogen.
24. describe the stimulation of glycogenolysis in the liver.
25. describe what happens roughly 4 hours after a meal.
26. describe what happens during prolonged starvation.
27. how long does it take to deplete liver glycogen stores? (and therefore halt glycogenolysis)
answers
1. liver releases glucose into the blood via glycogenolysis and gluconeogenesis.
2. the process by which glucose is created in the liver from non carbohydrate sources.
3. lactate, glycerol, and amino acids- particularly alanine.
4. lactate is produced by anaerobic glycolysis through reduction of pyruvate or by adipocytes in the fed state or by red blood cells. lactate is oxidized into pyruvate, which is a precursor for gluconeogenesis.
5. alanine is produced in the muscle from other amino acids (whenever insulin is low or stress hormones are high) and from glucose. it is converted to pyruvate via alanine aminotransferase.
6. glycerol is released from adipose tissue whenever insulin levels are low or stress hormones are high. it is converted to DHAP, which is a gluconeogenetic intermediate (as well as a glycolytic one)
7. pyruvate is created from alanine or lactate in the cytosol, and then travels into the mitochondria, where it is carboxylated to oxaloacetate via pyruvate carboxylate (an anaplerotic reaction of the TCA cycle). oxaloacetate is then transaminated to aspartate or reduced to malate and transported back out into the cytosol, and reformed back into oxaloacetate (via oxidation or transamination). in the cytosol, oxaloacetate is decarboxylated by phosphoenolpyruvate carboxylkinase to form PEP.
8. the reduction of oxaloacetate into malate requires reducing equivalents; if the mitochondria has need for reducing equivalents for other reactions, it will use the other venue, the conversion to aspartate.
9. PEP is converted to fructose 1,6 bisphophate through a reversal of the glycolytic reactions. PEP is converted into 2-phosphoglycerate, to 3-phosphoglycerate, to 1,3 bisphosphoglycerate, and reduced to G3P. for every two molecules of G3P produced, one isomerizes to DHAP. G3P and DHAP condense to form fructose 1,6 bisphosphate.
10. fructose 1,6 bisphosphate has a phosphate removed by fructose 1,6bisphosphatase to form fructose 6 phosphate. fructose 6 phosphate is isomerized to glucose 6 phosphate by phosphoglucose isomerase. glucose 6 phosphate has a phosphate removed by glucose 6-phosphatase, producing glucose.
11. glycerol is converted to glycerol 3-phosphate via glycerol kinase, and then oxidized to DHAP.
12. prolonged exercise, stress, and a high protein diet.
13. OAA to PEP, fructose 1,6 bisphosphate to fructose 6 phosphate, glucose 6 phosphate to glucose. all three reactions use regulatory enzymes which are not involved in the reverse glycolytic pathway.
14. during the fasting state, fatty acids are released from adipose tissue and undergo beta oxidation, producing NADH, acetyl CoA, and ATP. the higher ATP / ADP ratio phosphorylates pyruvate dehydrogenase into the inactive form.
15. fatty acid oxidation produces acetyl CoA, which activates pyruvate carboxylase.
16. glucagon is released during fasting and EP is released during exercise/stress, both of which stimulate production of cAMP, which increases transcription of PEPCK genes.
17. pyruvate kinase is the enzyme that catalyzes the conversion of PEP back into pyruvate. when glucagon levels are high, pyruvate kinase is phosphorylated and inactive through a mechanism involving cAMP and protein kinase A.
18. this reaction occurs via the fructose 1,6 bisphosphotase enzyme, and normally would compete with the reverse reaction from glycolysis, fructose 6-phosphate to fructose 1,6 biphosphate via PFK-1. however, under conditions favoring gluconeogenesis, the enzymes that stimulate PFK-1 are inactive, allowing the reaction to head towards the production of glucose.
19. low insulin and glucose levels deactivate the enzyme for the glycolytic forward reaction and allow the glucose synthesis to occur.
20. for every mole of glucose that is produced, 6 moles of ATP and 2 moles of NADH are used. 2 moles of ATP at the conversion of pyruvate to oxaloacetate, 2 moles of ATP at the conversion of oxaloacetate to PEP, 2 moles of ATP at the conversion from 3-phosphoglycerate to 1,3 bisphosphoglycerate, and 2 moles of NADH at the reduction of 1,3 bisphospholycerate to G3P. (2 moles at each reaction because 2 molecules of pyruvate combine into one molecule of glucose)
21. fasting: 80-100mg/dL. right after a meal: up to 140mg/dL. 2 hours after a meal: back to 80-100mg/dL. starvation: not lower than 65mg/dL.
22. during a meal, the high glucose concentration in the blood stimulates the beta cells of the pancreas to increase insulin production. glucagon levels decrease in response to a high carbohydrate meal but increase in response to a high protein meal.
23. glycerol is released from adipose whenever levels of insulin are low and levels of glucagon is high-- and is converted into DHAP. glucagon is a hormone released by the alpha cells of the pancreas in response to decreasing blood glucose levels-- stimulating gluconeogenesis. glucagon also activates production of cAMP in liver cells, which activates protein kiase A, which inactivates glycogen synthase-- thus high glucagon levels inhibit glycogen production. glycogen is synthesized from glucose and stored in the liver.
24. high glucagon levels stimulate adenylate cyclate, which synthesizes cAMP. cAMP activates protein kinase A, which inactivates glycogen synthase, and activates phosphorylase kinase. phosphorylase activates phosphorylase b, which converts glycogen to glucose 1-P, which is then converted to glucose 6-P and then free glucose in the liver, which can then enter the blood.
25. in addition to supplementing blood glucose levels with glycogenolysis, gluconeogenesis is stimulated by the release of precursor material such as glycerol, alanine, and lactate from peripheral body tissues.
26. the body switches to fatty acid and ketone body oxidation and requires much less glucose.
27. ~30 hours
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