Liver Biosynthetic Functions Flashcards
1
Q
Describe the structure of the liver.
A
2
Q
Discuss the function of liver: Metabolism.
A
Of protein, fats and carbs
- Glycogen synthesis (glycogenesis).
- Glycogen breakdown (glycogenolysis).
- Gluconeogenesis.
- Fatty acid metabolism (Hydrolysis of triglycerides to release glycerol and fatty acids).
- Deamination and transamination of amino acids.
- Removal of ammonia from body by synthesis of urea.
3
Q
Describe ammonia detoxification in the liver.
A
4
Q
Discuss the function of liver: Synthesis.
A
- Plasma proteins (including albumin).
- Coagulation factors.
- Haem.
- Lipoproteins.
- Bile acids (primary).
5
Q
Discuss the function of liver: Excretion and detoxification.
A
- Bilirubin.
- Amino acids & NH3 (Urea Cycle).
- Cholesterol and steroid hormones.
- Drugs.
- Toxins.
6
Q
How does the liver regulate metabolism fed and fasting states?
A
- Fed: Uses ingested glucose and amino acids.
- Fasting state: Processes nutrients to generate
an alternative energy source.
7
Q
Discuss Fat biosynthesis in the liver.
A
- Most lipoproteins synthesised in liver.
- Converting excess carbohydrates and proteins into fatty acids and triglyceride (exported and stored in adipose tissue).
- Synthesis of large quantities of cholesterol and phospholipids …some packaged with lipoproteins and made available to rest of body.
- Remainder excreted in bile as cholesterol or as bile acids.
8
Q
Discuss protein biosynthesis in the liver.
A
- Liver tissue proteins:
- Structural proteins
- Enzymes - Exported proteins
- Plasma proteins (Albumin, a & b globulins and fibrinogen).
*Hepatocytes are responsible for the synthesis of most plasma proteins and synthesis of non-essential amino acids (eg. glutamine).
9
Q
Discuss Albumin synthesis.
A
- Synthesised only in hepatic cells.
- 15 g/d in healthy adult.
- The predominant serum-binding protein.
10
Q
Function of albumin.
A
- Transports many substances eg. bilirubin, fatty acids, metals, ions, hormones, exogenous drugs.
- Provides 75-80% of the oncotic pressure.
11
Q
What is oncotic pressure?
A
- The osmotic pressure exerted by large molecules, serves to hold water within the vascular space.
12
Q
What is the distribution of albumin?
A
- Enters intravascular space from hepatocytes:
1. Enters hepatic lymphatic system and into the thoracic ducts.
2. Passes directly into sinusoids after traversing Space of Disse (Perisinusoidal space). - Intravascular space:
1. T1/2 ~17 days, degradation rate about 4% per day.
2. Some pathological conditions increase daily loss from plasma: nephrosis, lymphoedema, ascites, oedema, intestinal lymphangioectasia.
3. Vascular compartments of muscle, skin, liver, gut, and other tissues. - Extravascular spaces:
1. All tissues, with majority being distributed in the skin.
13
Q
What are other plasma protein synthesised by liver?
A
- a & b globulins
- Acute phase proteins e.g. crp.
- Coagulation factors V, VII, IX, X, XIII, I, II.
14
Q
Discuss a & b globulins.
A
- Structure : glycoproteins.
- Cleared by asialoglycoprotein receptors on surface of hepatocytes.
- Function:
- Variable, transport proteins, protease inhibitors, clotting factors.
- Plasma levels can be indicative of disease
15
Q
What causes decreased a & b globulins?
A
- Genetic disorders (eg. a1-antitrypsin deficiency).
- Malnutrition.
16
Q
What causes increased a & b globulins?
A
- Acute phase reactants: post- inflammatory or traumatic conditions.
- Retention of high MW proteins following
compensatory increased synthesis (eg. a2-macroglobulin)
17
Q
What are the types of acute phase proteins?
A
- Negative acute phase proteins: transferrin.
- Positive acute phase proteins: (CRP) & α1- antitrypsin.
*CRP can be elevated > 1,000 fold.
18
Q
What is Haem synthesis?
A
- A chemical structure in which a ferrous ion is chelated in the centre of a heterocyclic organic ring called a Porphyrin ring (protoporphyrin lX).
- Porphyrins are a group of organic compounds (incl. haem).
19
Q
What is the function of haemoproteins?
A
- Multiple haemoproteins with diverse functions
Eg. oxygen transport, catalysis, electron transfer.
20
Q
What are the important enzymes in the synthesis of Haem.
A
- d- aminolevulinic acid (ALA) synthase.
- d- aminolevulinic acid (ALA) dehydratase.
- Uroporphyrinogen synthase (hydroxymethylbilane synthase / PBG deaminase) + UP-cosynthase.
21
Q
What is the function of d- aminolevulinic acid (ALA) synthase in haem synthesis?
A
- Mitochondrial enzyme.
- Rate limiting step in haem biosynthesis
- Inhibited by free non-protein bound Haem by negative feedback.
- Inducible enzyme
22
Q
What is the function of d- aminolevulinic acid (ALA) dehydratase?
A
- Cytoplasmic enzyme.
- Converts 2 x ALA molecules to porphobilinogen (PBG)
- Enzyme contains sulphydryl groups so is sensitive to inhibition by lead (Pb2+) and other heavy metals (get elevated ALA-synthase and symptoms of lead poisoning).
23
Q
What is the function of Uroporphyrinogen synthase I + UP-cosynthase?
A
- One molecule of uroporphyrinogen formed from 4 molecules of porphobilinogen (PBG).
- Two different molecules formed: UP l and UP lll.
- UP lll = naturally-occurring porphyrin
- One pyrrole ring ‘flipped’ by UP-cosynthase
24
Q
Discuss the formation of haem.
A
- Decarboxylation of acetate & propionate side groups to methyl & vinyl groups.
- Transfer into mitochondria.
- Chelation of iron.
25
How is haem and globin synthesis regulated?
Haem:
- Inhibits activity of d-ALA synthase.
- Diminishes transport of d-ALA synthase from cytoplasm to mitochondria after synthesis of enzyme.
- Represses production of d-ALA synthase by regulating gene transcription.
- Stimulates globin synthesis to ensure levels of free haem remain low.
**Inhibition of d-ALA synthase and stimulation of globin synthesis is important for balancing hb production.
26
What are the metabolic consequences of impaired enzyme activity?
27
What are defects of haem synthesis?
1. The Porphyrias:
- Group of metabolic disorders caused by partial defects in one of the haem biosynthetic enzymes causing overall reductions in haem synthesis.
28
What is the effect of the Porphyrias?
- Accumulation of toxic intermediate products.
- Less haem means positive feedback to boost the pathway and even more toxic intermediates formed.
- Can be photosensitive or non-photosensitive (in skin = lesions/ blisters).
**A complete deficiency in haem would be fatal.
29
What is Acute intermittent porphyria (AIP)?
- Defect in uroporphyrinogen synthase I (hydroxymethylbilane synthase/ PBG deaminase).
- 50% reduction in enzyme activity.
- 90% with genetic trait never present.
- Haem synthetic pathway is terminated early, at PBG.
- Clinical manifestations due to accumulation of ALA and PBG.
30
What causes acute attacks of (AIP)?
- Induction of Haem protein Cytochrome P450 synthesis:
1. Enzyme inducing drugs (eg. barbiturates, phenytoin).
2. Haem proteins contain >60% of haem in liver.
3. Induction depletes small pool of free unbound haem.
4. De-repression of d-aminolevulinic acid (ALA) synthase (loss of negative feedback to inhibit further pathway activity).
5. ALA and PBG (substrates for UP synthase) accumulate.
31
What is the treatment of AIP?
- Haematin: derived from Haem (haem hydroxide) or Haemin (Hemin/Panhematin).
- Represses d-aminolevulinic acid (ALA) synthase.
32
What are the cutaneous manifestations of Porphyrias (Porphyria cutanea tarda (PCT))?
- Features of PCT: Itching, erythema, blistering
- Causes: Deficiency in uroporphyrinogen decarboxylase.
- Consequences:
1. Accumulation of Porphyrins
2. Accumulation of Porphyrinogens: non-enzymatically converted to porphyrin.
**Photo-excited by sunlight, causing cellular damage.
