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GI Week 5 - WLB > Liver Biochemistry - Skildum > Flashcards

Liver Biochemistry - Skildum Flashcards

1
Q

What are the ten biochemical functions of the liver?

A
  1. Receiving and processing nutrients
  2. Detoxifying xenobiotics and metabolites
  3. Regulating blood glucose
  4. Synthesizing and exporting cholesterol and triacylglycerol
  5. Processing nitrogen through the urea cycle
  6. Synthesizing ketone bodies
  7. Synthesizing nucleotides
  8. Synthesizing blood proteins
  9. Synthesizing glycoproteins and proteoglycans
  10. Pentose phosphate pathway
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2
Q

Which amino acids transport excess nitrogen from peripheral tissues to the liver?

A

Glutamine and Alanine

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3
Q

What are hepatic stellate cells? Function?

A
  • storage sites of lipids, especially esterified vitamin A
  • When stellate cells are activated, they lose vitamin A stores and deposit collagen in the Space of Disse.
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4
Q

What are hepatic pit cells? Function?

A

liver associated lymphocytes

These natural killer cells protect against viruses and tumor cells.

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5
Q

What are Kupffer cells?

A

endocytic, phagocytic macrophages

Source of inflammatory mediators that contribute to liver injury.

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6
Q

How do substances enter the liver? Leave the liver?

A
  • Substances enter liver through the blood.
  • Substances leave the liver through the blood or the bile duct.
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7
Q

What does the liver convert excess protein and carbohydrates into?

A

blood proteins, glucose, and VLDL

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8
Q

What is a xenobiotic?

A

a foreign chemical substance found within an organism that is not normally naturally produced by or expected to be present within that organism

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9
Q

What are Phase I and Phase II reactions that aid in detoxifying xenobiotics and metabolites?

A
  • Phase I reactions add hydroxyl groups to substrates
    • reduction
    • oxidation
    • hydroxylation
    • hydrolysis
  • Phase II reactions add sulfate, methyl groups, glutathione, or glucuronate to the hydroxyl group
    • conjugation
    • sulfation
    • methylation
    • glucouronidation
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10
Q

What enzymes are important in phase I metabolizing enzymes?

A
  • Cytochrome P450 enzymes
    • e.g. Cyp3A4 metabolizes many drugs, including some statins.
    • If two Cyp3A4 substrates are ingested, the one with the higher affinity for Cyp3A4 will be metabolized faster.
    • Grapefruit juice contains an inhibitor of Cyp3A4.
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11
Q

What is the most common cause of acute liver failure?

A

Acetaminophen toxicity

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12
Q

Acetaminophen solubility can be increased by glucurodination and sulfation independent of cytochrome P450 enzymes. What provides the sulfur for the sulfotransferases?

    1. cysteine
    1. PAPS (3’phosphoadenosine-5’phosphosulfate)
    1. cobalamin
    1. methionine
    1. reduced glutathione
A

Sulfotransferases use PAPS as a sulfur donor.

(in Phase II reactions)

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13
Q

How does Acetaminophen poisoning cause liver failure?

A
  • Cyp2E1 converts acetaminophen to NAPQI, which can create adducts on cell proteins and kill cells.
    • ​NAPQI can be excreted in urine if adequate supply of glutathione
    • Ethanol incudes Cyp2E1 expression and increases the rate of NAPQI production.
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14
Q

What drug is an inhibitor of the CYP2E1 enzyme?

A

Cimetidine (Tagamet)

(H2 receptor blocker)

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15
Q

Macrophages that mediate inflammation in the liver are called _________?

A

Kupffer cells

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16
Q

How does chronic overconsumption of ethanol cause liver damage?

A
  • Acetaldehyde produced by ADH and Cyp2E1 is responsible for the long term damage to the liver associated with ethanol consumption.
  • Kupffer cells get irritated by acetaldehyde
    • activated Kupffer cells stimulate Stellate cells via TGF-beta
      • stimulated Stellate cells lay down extracellular matrix collagen
        • results in fibrosis of the liver
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17
Q

How does the liver regulate blood glucose?

A
  • Fed:
    • The liver converts excess carbohydrates to storage forms: triglyceride and glycogen.
    • Insulin →
      • Triglyceride synthesis
      • Glycogen synthesis
      • Active glycolysis
  • Fasted
    • The liver converts glycogen and amino acids to glucose.
    • Glucagon →
      • Glycogen degradation
      • Gluconeogenesis
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18
Q

What does phosphoglucomutase-1 do?

A

interconverts glucose 1-phosphate and glucose 6-phosphate

  • patients with mutations in this enzyme results in impaired fasting blood glucose
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19
Q

What is cholesterol synthesized in the liver used for?

A
  • bile salts
  • cell membranes
  • to store fatty acids
  • steroid hormones
20
Q

What is excess carbohydrate converted into in the liver?

A
  • fatty acids
    • get packaged as triacylglycerol in VLDL particles by the liver
    • IDL and LDL particles can be recycled by the liver.
21
Q

What does the liver do with excess nitrogen generated from amino acid catabolism?

A
  • converts urea for excretion
    • via urea cycle
    • One of urea’s nitrogens comes from free ammonia and the other comes from aspartate
22
Q

How does excess nitrogen from the peripheral tissues get transported to the liver?

A

Excess nitrogen is transported from peripheral tissues to the liver in the form of the amino acid glutamine.

(alpha-KG + NH4+ → Glutamate + NH4+ → Glutamine)

23
Q

What event occurs after Wnt binds its receptor?

    1. b-catenin is ubiquinated and destroyed.
    1. Gut epithelial cells exit the cell cycle and differentiate.
    1. P21 and p27 transcription increases.
    1. APC phosphorylates b-catenin
    1. b-catenin translocates to the nucleus
A

Beta-catenin translocates to the nucleus

24
Q

Blood from intestines enters the liver through the ________.

A

Portal Vein

25
Q

What happens to the nitrogen that results from the breakdown of skeletal muscle proteins?

A
  • Breakdown of skeletal muscle protein → Nitrogen transferred by Glutamine → to blood from gut from gut → to periphery → to portal vein
    • Glutamine + Glutaminase → Glutamate + NH4+
    • NH4+ + Carbamoyl phosphate synthetase I (CPSI)
26
Q

What would happen if the amount of glutamine entering the liver exceeded the capacity of carbamoyl phosphate synthase (CPS1)?

A
  • NH4+ would build up in the liver
27
Q

Where is Glutaminase and CPSI expression the highest?

A

Periportal cells

28
Q

How is glutamine synthase expression regulated?

A

Glutamine synthase is transcriptionally activated by beta catenin.

29
Q

What is Wnt signaling important for?

A

epithelial cell development and differentiation

30
Q

What cells in the liver are secreting Wnt?

A

central vein endothelial cells

31
Q

Maintaining blood glucose while fasting is dependent on what cycle?

A

Urea Cycle

  • Helps process nitroge
  • Nitrogen removed from Amino Acids to make glucose via gluconeogenesis
32
Q

A 15 year old female has short stature, episodic hypoglycemia, and myopathy. Physical exam reveals a bifid uvula, and she does not show any signs of entering puberty.

What system

A

GI/hepatobiliary

33
Q

What is the inheritance pattern of phosphoglucomutase 1 deficiency?

A

Autosomal recessive

34
Q

What symptoms may be present in PGM1 deficiency?

A
  • Growth retardation
  • Amennorrhea
  • Hepatopathy
  • Bifid uvula
  • Myopathy
  • Hypoglycemia
  • Dilated cardiomyopathy
35
Q

Why is PGM1 important?

A
  • Phosphoglucomutase (PGM1) interconverts glucose 1-phosphate and glucose 6-phosphate.
    • PGM1 is essential for glycogenolysis and glyocogen synthesis.
      • mainly (G-1-P)
    • PGM1 is also important for generating UDP-galactose, a glycosylation intermediate.
      • charged nucleotides
36
Q

What are the excretory / detoxification function tests when evaluating liver function?

A
  • Serum bilirubin
    • conjugated + unconjugated increased: liver damage
    • uncojugated only increased: hemolysis
  • Urine bilirubin
    • all conjugated
    • urine bilirubin drops before serum bilirubin
  • Serum ammonia
    • may indicate urea cycle problems
37
Q

What can elevated bilirubin indicate?

A
  • Elevated bilirubin can indicate increased red cell breakdown or decreased conjugating capacity in the liver.
  • “direct bilirubin” = conjugated
  • “indirect bilirubin” = unconjugated
38
Q

What happens to bilirubin in the liver?

A
  • Bilirubin is glycosylated by the addition of 2 glucuronates, in the form of UDP glucuronate.
    • The enzyme glucuronosyl transferase catalyzes this reaction.
  • The bilirubin diglucuronide is more soluble, and can be excreted in bile or urine.
  • Glucuridination is not the rate limiting step in bilirubin elimination– transport across the canilicular membrane is.
39
Q

What enzyme tests reflect damage to hepatocytes?

A
  • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)
    • ALT is most specific for liver damage
    • if AST:ALT ≤ 1, suggests acute hepatocellular disorder
    • if AST:ALT ≥ 2, suggests liver damage secondary to alcohol abuse
  • Lactate dehydrogenase (LDH)
    • not specifice for liver
40
Q

What enzyme tests reflect cholestasis (bile duct blockage)?

A
  • alkaline phosphatase
    • localized to canilicular membrane of hepatocytes
    • not specific for cholestasis (or liver disease)
  • 5’ nucleotidase
    • localize to canilicular membrane of hepatocytes
  • gamma-glutamyltranspeptidase
    • localized in bile duct epithelial cells
    • important for glutathione metabolism
41
Q

What tests measure the liver’s biosynthetic capacity (proteins made by the liver)?

A
  • serum albumin
    • has a long half life, so it is not good for acute liver damage
    • decreased albumin may reflect malnutrition rather than liver disease
  • serum globulins
    • produced by B lymphocytes (gamma-globulin) and hepatocytes (alpha and beta globulins)
    • gamma-globulins increase with liver disease; possibly due to increased antigenic material entering hepatic circulation.
      • Increased IgA: alcoholic liver disease
      • Increased IgG: autoimmune hepatitis
      • Increased IgM: primary biliary cirrhosis
  • coagulation factors
    • Elevated prothrombin time suggests defect in synthesizing fibrinogen et al.
42
Q

Why is the pentose phosphate pathway so important in the liver?

A
  • Create NADPH
    • NADPH powers biosynthetic and detoxification reactions that occur in the liver
      • Detoxifying xenobiotics and metabolites
      • Synthesizing and exporting cholesterol and triacylglycerol
    • Nucleotides are used for nucleic acids and cofactors.
43
Q

How is glutamine synthase expression regulated?

    1. Glutamine synthase is transcriptionally repressed by beta catenin.
    1. Glutamine synthase is transcriptionally activated by beta catenin.
    1. Glutamine synthase is ubiquinated by SCF and degraded by the proteosome.
    1. Glutamine synthase nuclear localization is augmented by GSK3beta.
    1. Glutamine synthase translation is increased by EF1a.
A
  1. Glutamine synthase is transcriptionally repressed by beta catenin.
44
Q

Acetaminophen overdose causes death of hepatocytes surrounding the central vein. What molecule will be elevated in the blood of a patient suffering from acetaminophen toxicity?

    1. Glucuronate
    1. Glutamine
    1. PAPS
    1. Ammonia
    1. Alanine
45
Q

A 42 year old female has been binge drinking for two weeks. She took the recommended dose of Tylenol because of a headache. The next day, she became lethargic, vomitted frequently, and developed severe pain. What is the most likely cause of the patient’s symptoms?

    1. Hyperglycemia
    1. Inhibition of acetaminophen metabolism by ethanol
    1. Hypergalactosemia
    1. Acceleration of acetaminophen metabolism by ethanol
    1. Decrease in inflammatory prostaglandins
A
  1. Acceleration of acetaminophen metabolism by ethanol
46
Q

What is the cofactor for alanine aminotransferase (ALT)?

    1. Biotin
    1. Cobalamin
    1. NADH
    1. FAD(2H)
    1. Pyridoxal phosphate
A
  1. Pyridoxal phosphate
47
Q

What is the cofactor for lactate dehydrogenase?

    1. Biotin
    1. Cobalamin
    1. NADH
    1. FAD(2H)
    1. Pyridoxal phosphate

GI Week 5 - WLB (16 decks)

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