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Biochem Quiz 4 > Hepatic Function > Flashcards

Hepatic Function Flashcards

1
Q

CHARACTERISTICS OF THE LIVER

A

• Portal circulation, 25% of cardiac output, gives liver the first choice on absorbed nutrients and toxic substances, higher concentrations of insulin and glucagon. The fenestrated endothelium permits passage of proteins, lipoproteins and chylomicron remnants. Hepatic artery provides oxygen.

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2
Q

REPLACEMENT of LIVER FUNCTIONS.

A
  • Artificial Liver systems
  • Liver transplant (from dead donors, genetically modified animals?)
  • Partial liver transplant (from living donors)
  • Portal hepatocyte colonization (from healthy donors, or self after genetic engineering, stem cells?)
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3
Q

Mechanisms of Blood Glucose Maintenance

A
  • Storage of Glycogen
  • Release of glucose from stored glycogen.
  • Conversion of other sugars to glucose
  • Gluconeogenesis
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4
Q

Storage of Glycogen

A
  • Highly branched glycogen permits rapid mobilization
  • Glycogen synthase needs primer: glycogenin
  • Insulin does not affect glucose transport in liver
  • Liver contains hexokinase (as other tissues)(km<0.l mM), but 80% of phosphorylation is catalyzed by liver-specific glucokinase, sensitive to glucose concentration (Km = 10 mM)
  • Contrary to hexokinase, glucokinase is not inhibited by its product (Glc-6-P). Thus, in liver, phosphorylation limits uptake. Once glycogen particles are replenished, Glc-6-P is largely channeled into lipogenesis.
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5
Q

Release of glucose from stored glycogen.

A

• Glucose-6-phosphatase occurs only in liver and kidney. Because of its larger mass and glycogen content, release of glucose between meals is largely a liver function
• Contrary to muscle, in the dephosphorylated state Hepatic glycogen phosphorylase is not stimulated by AMP, but in the phosporylated state it is inhibited by glucose.
•

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6
Q

Glycogen storage diseases

A
  • Type I (Von Gierke disease)
  • Type II (Pompe’sdisease)
  • Type III (Cori’s disease)
  • Type IV (Andersen’s disease)
  • Type V( McArdle’s disease)
  • Type VI (Hers’disease)
  • Type VII
  • Type VIII
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7
Q

Type I (Von Gierke disease)

A
  • Defective enzyme: Glucose-6-phosphatase
  • Organs affected: Liver and Kidney
  • Clinical features: Large liver, fasting hypoglycemia
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8
Q

Type II (Pompe’sdisease)

A
  • Defective enzyme: Lysosomal amylase
  • Organs affected: All organs
  • Clinical features: Cardiorespiratory failure before 2
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9
Q

Type III (Cori’s disease)

A
  • Defective enzyme: Debranching enzyme
  • Organs affected: Muscle , Liver
  • Clinical features: Like Type I but milder course
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10
Q

Type IV (Andersen’s disease)

A
  • Defective enzyme: Debranching enzyme
  • Organs affected: Liver
  • Clinical features: Cirrhosis: death before 2yrs
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11
Q

Type V( McArdle’s disease)

A
  • Defective enzyme: Glycogen phosphorylase
  • Organs affected: Muscle
  • Clinical features: Cramps after exercise
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12
Q

Type VI (Hers’disease)

A
  • Defective enzyme: Glycogen phosphorylase
  • Organs affected: Liver
  • Clinical features: Like Type I but milder course
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13
Q

Type VII

A
  • Defective enzyme: Phosphofructokinase I
  • Organs affected: Muscle
  • Clinical features: Like Type V but milder
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14
Q

Type VIII

A
  • Defective enzyme: Phosphorylase kinase
  • Organs affected: Liver
  • Clinical features: Mild liver enlargment; mild hypoglycemia
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15
Q

Conversion of other sugars to glucose.

Galactose

A

• Galactose is half of the carbohydrates in milk
• Conversion of Galactose to glucose:
Galactose -(1)-> Gal-1 P -(2)-> Glucose-1 P -(3)-> Glucose-6 P
1) Gal kinase
2) P-gal uridyl transferase
3) Epimerase
• Genetic deficiency of P-gal uridyl transferase is far more serious than Gal kinase because of accumulation of Gal-1 P which is toxic because of possible sequestration of intracellular Pi

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16
Q

Conversion of other sugars to glucose.

Fructose

A

• Fructose can be up to l/3 of total dietary carbohydrates, most as part of sucrose
• A minor portion of that fructose is used by muscle and liver through hexokinase via fructose-6 P and the normal glycolytic pathway
Fructose -(hexokinase)-> fructose-6 P
• The majority is converted to Glyceraldehyde:
Fructose -(1)-> Fructose-1 P -(2)-> Glyceraldehyde
1) Fructokinase
2) Fructose-1-P aldolase
• Genetic deficiency of Fructose-1-P aldolase is far more serious than Fructose kinase because of accumulation of Fructose-1 P which is toxic because of possible sequestration of intracellular Pi

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17
Q

Two Warnings about Fructose

One

A

Ingestion of excessive amounts of fructose (say, children drinking lots of apple cider in a hot summer day) can cause diarrhea because the absorption of fructose through the GLUT5 transporter is not very effective. This characteristic may be a protective mechanism, because excessive absorption of fructose could be damaging to the liver

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18
Q

Two Warnings about Fructose

Two

A
  • Decades ago, it had been fashionable in some countries to consider replacing glucose by fructose as an intravenous nutrient in diabetics. Never do that!
  • Large amounts of fructose are preferentially taken up by hepatocytes. Fructokinase, however, is a much more efficient enzyme than fructose-1-P aldolase even when this enzyme is not defective. That makes fructose-1-P aldolase rate-limiting. The consequence of the excessive uptake of fructose is the hepatic accumulation of fructose-1-P, which is deleterious to the liver (just as with much smaller amounts of fructose, when there is a genetic defect in fructose-1-P aldolase)
19
Q

Gluconeogenesis

A

• Glucosw can be made in liver from non-sugar substrates, such as:
1) lactate
2) amino acids
3) glycerol.
• In the postabsorptive state, gluconeogenesis from lactate in the ‘Cori Cycle’, generates about 15% of liver glucose production (increased during anaerobic exercise).
• Gluconeogenesis from amino acids, is only 10% of liver glucose production in postabsorptive conditions, but it is vastly increased after a protein-rich meal (the only source of carbohydrates in carnivorous diets) or during starvation (in which case 50% is from alanine)

20
Q

Gluconeogenesis

Regulation

A
  • Availability of lactate (anaerobic exercise) or excess amino acids (after a protein-rich meal or because of net proteolysis in liver and muscle during starvation).
  • Modulation by cAMP of pyruvate kinase and of the conversion of Frc-l,6 P to Frc-6 P (via Frc-2,6 P )
21
Q

Gluconeogenesis and Starvation

A
  • After several days of starvation, hepatic capacity for gluconeogenesis is increased by induction of PEP carboxykinase, glucose-6 phosphatase and many transaminases (by glucocorticoids and the release of the inhibitory effect of insulin through FOXO1 phosphorylation).
  • Gluconeogenesis depends on the availability of cytosolic NAD+ for the reoxidation of malate.
  • Combination of starvation and ethanol is a frequent cause of hypoglycemia because cytosolic oxidation of ethanol leads to fully reduced cytosolic NADH. Because of competition for the same cytosolic NAD+, starvation decreases ethanol metabolism, ethanol plus starvation leads to production of lactic acid, and ethanol inhibits liver glycolysis.
22
Q

NITROGEN METABOLISM.

Synthesis of urea

A

Increased urea synthesis results from increased supply of amino acids to the liver (from the diet after a protein-rich meal, from muscle protein degradation during starvation). Increased Glu results in an expansion of intramitochondrial N-ac-Glu, which stimulates carbamyl-P synthetase. Over a period of days liver adapts to protein-rich diets or starvation with induction of all urea cycle enzymes (re: Dr Barlowe). Liver failure or defects in any of the urea cycle enzymes may result in high blood NH3, which is toxic to the brain.

23
Q

NITROGEN METABOLISM.

Catabolism of excess dietary amino acids

A

Amino acid carbons in excess are used for glucogenesis, lipogenesis or ketogenesis depending on the condition and the nature of the C chain.

24
Q

NITROGEN METABOLISM.

Conversion of extrahepatic amino acid C to glucose in the postabsorptive state

A

In this state, excess amino acids are generated primarily in muscle by autophagy. The branched chained amino acids (Leu, Ile, Val) are oxidized in muscle . Their amino N is transferred to pyruvate to make alanine (Ala). Ultimately, Ala transports C (from muscle glycolysis) and amino acids N to the liver, where it is converted to glucose and urea.

25
Q

NITROGEN METABOLISM.

Synthesis of non-essential amino acids

A

A major but not exclusive hepatic function. After a meal, it is in the liver where most of the ‘nitrogen shuffling’ occurs, by which N from abundant dietary amino acids is utilized to synthesize those poorly represented in the diet.

26
Q

NITROGEN METABOLISM.

Oxidation of hipoxanthine and xanthine to uric acid

A

Uric acid from endogenous purines is made in the liver. Xanthine oxidase is also present in intestinal epithelium, where most ingested purines are oxidized.

27
Q

NITROGEN METABOLISM.

Fine-tuned regulation of amino pools

A

Regulation of hepatic protein turnover is the most important factor in the acute regulation of amino acid pools. Rapid changes in protein turnover permit storage of excess amino acids as additional liver protein, and the utilization of hepatic protein as a predominant source of amino acids for the body between meals.

28
Q

LIPID METABOLISM - Oxidation of Fatty Acids.

A

Most tissues (except brain and blood cells) use FA. Liver uses FA almost exclusively as source of energy, about 20 g/day (except after a CHO-rich meal or alcohol ingestion).

29
Q

LIPID METABOLISM - Ketogenesis

A

• Hepatocytes can synthesize but not oxidize ketone bodies. The enzymes necessary for β-oxidation of FA, and the conversion of the resulting AcCoA to acetoacetate and ß-OH butyrate are always present in the matrix of hepatic mitochondria.
• Ketogenesis results from abundant exogenous supply of FA to the hepatocytes, and
increased transport of those FA into the mitochondrial matrix. The resulting beta-oxidation of the FA floods the mitochondria with AcCoA in excess of what can be oxidized in the Krebs cycle. The excess AcCoA is converted to ketone bodies and exported.

30
Q

LIPID METABOLISM - Ketogenesis

Starvation

A

In starvation, ketogenesis is promoted by cAMP in adipocytes (lipolysis) and hepatocytes (inhibition of AcCoA carboxylase, lower malonyl CoA, increased carnitine-linked mitochondrial transport of FA). After 3 d of starvation production of ketone bodies reaches ca. 150 g/d

31
Q

LIPID METABOLISM - Ketogenesis

Ketogenic Diests

A
  • Ketogenesis may also result from ingestion of lipid-rich, carbohydrate-deprived diets (carnivorous diets, Atkins diet). In this case the FA are provided by the diet, not the adipocytes.
  • Ketogenic diets such as these have been used to ameliorate refractory epilepsy in children. One version of such diets is rich in coconut oil, which contains medium-chain FA that can bypass the carnitine-linked step in liver mitochondria, and thus may be consumed together with carbohydrates.
32
Q

LIPID METABOLISM

Lipogenesis: de novo synthesis of Fatty Acids

A
  • From excess dietary glucose (in humans mostly in liver, and in lactating mammary gland). Moderate influx of glucose and modest increase in insulin levels favor glycogen synthesis. Larger glucose influx and insulin direct the glucose ‘overflow’ to lipogenesis.
  • To provide AcCoa for FA synthesis, glucose must be first degraded to AcCoA (via pyruvate dehydrogenase).
  • The rate-limiting step in lipogenesis is the synthesis of malonyl CoA. Acetyl CoA carboxylase is modulated by citrate (+), insulin (+) and glucagon (-) .
  • Lipogenic enzymes are induced by insulin (SREBP-1c) and glucose metabolism (CHREBP)
33
Q

LIPID METABOLISM

Desaturation of Fatty Acids

A

The liver introduces double bonds in FA by a mixed function oxygenase in liver endoplasmic reticulum (desaturase + cytochrome b5 + NADH-cytochrome b5 reductase). Double bonds in any of the last 7 C must be provided in the diet (essential fatty acids)

34
Q

LIPID METABOLISM

Synthesis of VLDL and degradation of lipoprotein remnants

A
  • In the postabsorptive sate, the liver takes up ca. 70g of free fatty acids (FFA) per day, uses 20g as fuel and exports 50g in VLDL. Repackaging FFA to TG in VLDL permits a more efficient delivery to extrahepatic tissues (excessive FFA are potentially toxic to the heart).
  • Excessive FFA uptake or lipogenesis (obesity, diabetes type II), decreased FA oxidation (ethanol, a preferred alternative fuel), or impaired synthesis of VLDL (choline deficiency, many drugs, liver failure) can result in accumulation of hepatocyte triglycerides (fatty liver).
35
Q

LIPID METABOLISM

De novo synthesis and catabolism of choline

A

The synthesis of phosphatidyl-choline (=lecithin) from phosphatidyl-serine occurs only in liver. Other cells use choline as such (from the diet) via the CDP-choline salvage pathway, or albumin-bound lysolecithin produced by the action of LCAT on HDL (re: Chang). Liver is also the site of catabolism of excess choline.

36
Q

LIPID METABOLISM

De novo synthesis of cholesterol

A

The liver is the major but not exclusive site. Inhibition of hepatic synthesis by dietary cholesterol (via chylomicron remnants) or cholesterol re-uptake from the blood (via LDL receptors) are crucial to the control of total body cholesterol. A major point of regulation is the activity of hepatic HMG-CoA reductase (the main therapeutic target of statins). The synthesis of this enzyme and of the LDL receptors is induced by SREBP-2

37
Q

LIPID METABOLISM

Elimination of cholesterol

A

Cholesterol is not broken down in the body. The liver eliminates it in the bile, as such or as bile acids. The bile acids are largely recovered in the enterohepatic circulation. Binding to insoluble food fiber may promote fecal elimination of bile acids and depletion of body cholesterol

38
Q

SECRETION OF BILE AND ENTEROHEPATIC CIRCULATION.

A

Bile is secreted by hepatocytes and concentrated up to 30-fold in the gall bladder. The secretion of bicarbonate is stimulated by secretin. Reabsorbed bile acids stimulate their further secretion. Cholecystokinin stimulates gal bladder discharge. Most bile acids are conjugated. Together with P-lipids, they keep up to 1% cholesterol in micellar suspension. Cholesterol precipitation may result in gallstones (re: Chang). The bile serves also for the excretion of many other conjugated hydrophobic substances.

39
Q

CONJUGATION AND EXCRETION OF HYDROPHOBIC SUBSTANCES

A

The liver contains a number of enzymes capable of attaching hydrophilic moieties (amino acids and their derivatives, glutathione or modified sugars) to undesirable hydrophobic substances or catabolites. The major one is bilirubin. Heme is degraded to bilirubin in spleen macrophages. Bilirubin is transported in the plasma bound to serum albumin, taken up by hepatocytes, conjugated with two molecules of glucuronic acid and the conjugate is eliminated in the bile. Bilirubin is further modified by enteric bacteria to darker fecal pigments (stercobilin and urobilin)

40
Q

CONJUGATION AND EXCRETION OF HYDROPHOBIC SUBSTANCES

Jaundice

A

Serum levels of unconjugated (alcohol soluble or indirect) bilirubin increase in hemolytic or hepatic jaundice. Conjugated (water soluble or direct) bilirubin predominates in the serum in obstructive jaundice., and also after hepatocellular damage, when debris clog biliary canaliculi. Fecal pigments tend to increase in hemolytic jaundice (except in the neonate, where bacteria have yet not colonized the intestine). They decrease or disappear in hepatic and obstructive jaundice

41
Q

OXIDATION OF LIPID-SOLUBLE SUBSTANCES

A 
A major pathway for the hydroxylation of hydrophobic substances is catalyzed by a large group of enzymes known as heme-containing cytochrome P450s (CYPs). They use molecular oxygen (O2) and a reactive Fe++ in the heme (which is kept in the reduced form by a NADPH-dependent enzyme).
CYPs comprise dozens of different proteins, each with a characteristic broad specificity for a class of hydrophobic organic molecules. In nature, the substrates are primarily undesirable components of plants or soil, as well as endogenous sterol hormones. By hydroxylation, the liver makes these compounds more soluble, which facilitates their elimination in the bile or the urine.
42
Q

OXIDATION OF LIPID-SOLUBLE SUBSTANCES

Metabolism of Drugs

A

CYPs are of great importance in medicine because they are often involved in the metabolism of drugs and hormones. In most cases these are inactivated by hydroxylation. Sometimes, however, hydroxylation results in the activation of an inactive precursor (for instance, codeine -> morphine). The situation is further complicated by the fact that many CYPs are inducible by these or other drugs, substances in the food, smoking, etc.. The increased activity of induced CYPs may modify drastically the sensitivity of the body to drugs and potential toxic agents. This important topic will be thoroughly addressed in your Pharmacology course.

43
Q

SYNTHESIS AND DEGRADATION OF PLASMA PROTEINS.

A

A major portion of total liver protein synthesis is devoted to the synthesis of most plasma proteins, included albumin, globulins (except immunoglobulins), fibrinogen and coagulation factors, as well as lipoproteins. The liver is also the site for the lysosomal degradation of plasma glycoproteins.

44
Q

STORAGE OF IRON, VIT B12, D AND A

A

In addition to the storage of glycogen and some of the excess amino acids as hepatic proteins, the liver plays a major role in the storage of iron as ferritin and vitamins (A, D, B12)

Biochem Quiz 4 (4 decks)

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