Liver Biosynthetic Functions Flashcards
Describe the structure of the liver.
Discuss the function of liver: Metabolism.
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.
Describe ammonia detoxification in the liver.
Discuss the function of liver: Synthesis.
- Plasma proteins (including albumin).
- Coagulation factors.
- Haem.
- Lipoproteins.
- Bile acids (primary).
Discuss the function of liver: Excretion and detoxification.
- Bilirubin.
- Amino acids & NH3 (Urea Cycle).
- Cholesterol and steroid hormones.
- Drugs.
- Toxins.
How does the liver regulate metabolism fed and fasting states?
- Fed: Uses ingested glucose and amino acids.
- Fasting state: Processes nutrients to generate
an alternative energy source.
Discuss Fat biosynthesis in the liver.
- 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.
Discuss protein biosynthesis in the liver.
- 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).
Discuss Albumin synthesis.
- Synthesised only in hepatic cells.
- 15 g/d in healthy adult.
- The predominant serum-binding protein.
Function of albumin.
- Transports many substances eg. bilirubin, fatty acids, metals, ions, hormones, exogenous drugs.
- Provides 75-80% of the oncotic pressure.
What is oncotic pressure?
- The osmotic pressure exerted by large molecules, serves to hold water within the vascular space.
What is the distribution of albumin?
- 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.
What are other plasma protein synthesised by liver?
- a & b globulins
- Acute phase proteins e.g. crp.
- Coagulation factors V, VII, IX, X, XIII, I, II.
Discuss a & b globulins.
- 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
What causes decreased a & b globulins?
- Genetic disorders (eg. a1-antitrypsin deficiency).
- Malnutrition.
What causes increased a & b globulins?
- Acute phase reactants: post- inflammatory or traumatic conditions.
- Retention of high MW proteins following
compensatory increased synthesis (eg. a2-macroglobulin)
What are the types of acute phase proteins?
- Negative acute phase proteins: transferrin.
- Positive acute phase proteins: (CRP) & α1- antitrypsin.
*CRP can be elevated > 1,000 fold.
What is Haem synthesis?
- 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).
What is the function of haemoproteins?
- Multiple haemoproteins with diverse functions
Eg. oxygen transport, catalysis, electron transfer.
What are the important enzymes in the synthesis of Haem.
- d- aminolevulinic acid (ALA) synthase.
- d- aminolevulinic acid (ALA) dehydratase.
- Uroporphyrinogen synthase (hydroxymethylbilane synthase / PBG deaminase) + UP-cosynthase.
What is the function of d- aminolevulinic acid (ALA) synthase in haem synthesis?
- Mitochondrial enzyme.
- Rate limiting step in haem biosynthesis
- Inhibited by free non-protein bound Haem by negative feedback.
- Inducible enzyme
What is the function of d- aminolevulinic acid (ALA) dehydratase?
- 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).
What is the function of Uroporphyrinogen synthase I + UP-cosynthase?
- 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
Discuss the formation of haem.
- Decarboxylation of acetate & propionate side groups to methyl & vinyl groups.
- Transfer into mitochondria.
- Chelation of iron.
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.
What are the metabolic consequences of impaired enzyme activity?
What are defects of haem synthesis?
- The Porphyrias:
- Group of metabolic disorders caused by partial defects in one of the haem biosynthetic enzymes causing overall reductions in haem synthesis.
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.
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.
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.
What is the treatment of AIP?
- Haematin: derived from Haem (haem hydroxide) or Haemin (Hemin/Panhematin).
- Represses d-aminolevulinic acid (ALA) synthase.
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.
