GB 16. Liver Biosynthetic Functions Flashcards
What are the 3 main functions of the liver? (just list them)
[1] Metabolism
[2] Synthesis
[3] Excretion + Detoxification
What is involved with the Metabolism function of the liver?
- glycogen synthesis (glycogenesis)
- glycogen breakdown (glycogenolysis)
- gluconeogenesis
- fatty acid metabolism
metabolizes:
[1] Carbohydrates
[2] Fats
[3] Protein
What is involved with the Synthesis function of the liver?
- plasma proteins (including albumin)
- coagulation factors
- haem
- lipoproteins
- bile acids (primary)
What is involved with the Excretion + Detoxification function of the liver?
- bilirubin
- amino acids + NH3 (urea cycle)
- cholesterol and steroid hormones
- drugs
- toxins
What are the 3 “zones” in the liver?
Zone 1: Periportal Zone
- O2 rich
- has the portal tract, hepatic artery, bile duct + portal vein
Zone 2:
- space between Periportal and Perivenous zones
Zone 3: Perivenous Zone
- has the central hepatic vein
In which direction does the blood flow in the zones of the liver?
- it flows from the Periportal Zone to the Perivenous Zone
- from Zone 1 to Zone 3
What is ammonia detoxification? Why is it important?
- ammonia (NH3) is toxic to the CNS
- it is converted to urea in the liver (through the urea cycle)
- NH3 is also used to convert glutamate to glutamine in the liver
What is the overall mechanism of carbohydrate metabolism in the liver? What are the important pathways?
GOAL: maintain blood glucose
[1] Glycogenesis
- excess glucose after meal is taken up by liver and stored as glycogen
[2] Glycogenolysis
- glycogen broken down + glucose then exported into blood to go to tissues
- when low blood glucose levels arise
[3] Gluconeogenesis
- glucose synthesized from amino acids + non-hexose carbohydrates when glycogen reserves depleted
Explain the process of fat metabolism in the liver.
- hydrolysis of triglycerides releases 2 products:
(A) Glycerol - metabolized by glycolytic pathway
(B) Fatty Acids
- beta oxidized to acetoacetate (AcAc)
- AcAc then used as an energy source in remote tissues
Explain how proteins are metabolized in the liver (hint: there are 2 processes involved)
[1] deamination + transamination of amino acids
- conversion of non-nitrogenous part to glucose/lipid
(glucogenic or ketogenic amino acids)
[2] removal of ammonia from body by synthesis of urea
- ammonia is produced from leftover amino acids
- it is toxic to the CNS
What are some of the proteins (and protein components) that are synthesized in the liver?
[1] non-essential amino acids (e.g. glutamine)
[2] plasma proteins (e.g. albumin - contributes to oncotic pressure)
[3] clotting factors
[4] acute phase proteins
What are some of the fats that are synthesized in the liver?
[1] Triglycerides
- liver converts excess carbs + proteins into fatty acids and triglycerides (exported + stored in adipose tissue)
[2] Cholesterol + Phospholipids
- some packaged with lipoproteins and made available to rest of body
- remainder excreted in bile as cholesterol or as bile acids
[3] Lipoproteins
What are some other molecules/things that are synthesized in the liver?
[1] Ketones - beta-hydroxybutarate and acetoacetate - ^^ 2 types of ketones [2] Haem [3] Bile Acids [4] Urea [5] Nucleotide Precursors - e.g. purines + pyrimidines
List all the molecules/things that can be synthesized in the liver.
[1] Proteins/Protein Components [2] Carbohydrates [3] Fats [4] Ketones [5] Haem [6] Bile Acids [7] Urea [8] Nucleotide Precursors
What are the 2 categories of proteins that are synthesized by the liver?
[1] Liver-Tissue Proteins
- structural proteins
- enzymes
[2] Exported Proteins
- plasma proteins
- albumin
- alpha and beta globulins
- fibrinogen
Where is the plasma protein, Albumin, synthesized?
ONLY in hepatic cells
- approx. 15 g/d in healthy adult
- althought rate varies with physiologic stress
What is the function of albumin?
- transports many substances (e.g. bilirubin, fatty acids, metals, ions, hormoes, exogenous drugs…)
- provides 75-80% of the ONCOTIC PRESSURE
What is Oncotic Pressure?
the pressure driving fluid into the vessel due to the presence of plasma proteins INSIDE the vessel
- it forces the vessels closed
What is the opposite of oncotic pressure?
Hydrostatic Pressure/Blood Pressure
- it keeps the vessel open
- blood pressure pushing the walls outwards
In oedema, where is there a higher concentration of albumin? Inside or outside the blood vessels?
Outside the blood vessels
- drawing water into the tissues
What are alpha- and beta- globulins?
they are plasma proteins!
What is the structure of alpha- and beta- globulins?
glycoproteins
How are alpha- and beta- globulins cleared from the cell?
cleared by ASIALOGLYCOPROTEIN receptors on the surface of hepatocytes
What are some of the functions of alpha- and beta- globulins?
- transport proteins
- protease inhibitors
- clotting factors
If there is decreased alpha- and beta- globulins in the plasma what may this be indicative of?
- genetic disorders (alpha1-antitrypsin deficiency)
- malnutrition
If there is increased alpha- and beta- globulins in the plasma what may this be indicative of?
- acute phase reactants. post-inflammatory or traumatic conditions
- retention of high MW proteins following compensatory increased synthesis (alpha2-macroglobulin)
What are porphyrins?
a group of organic compounds which include haem
What is the chemical structure of haem?
a ferrous ion (Fe) is chelated in the centre of a porphyrin ring (heterocyclic organic ring)
Ferrous Ion is OXYGENATED, not oxidised! (Fe2+)
What are some of the functions of haemoproteins?
- oxygen transport
- catalysis
- electron transfer
What haemoprotein is synthesized in the bone marrow?
Haemoglobin
What haemoprotein is synthesized in the muscle?
Myoglobin
What haemoprotein is synthesized in the liver?
[1] Cytochrome P450 Proteins
[2] Catalase
What is the rate-limiting step in the synthesis of haem in the liver?
ALA Synthase
- first enzyme in haem synthesis
- rate-limiting step
- converts succinyl coA + Glycine TO ALA
What is the enzyme ALA synthase, which is used in the synthesis of haem, inhibited by?
inhibited by FREE, NON-PROTEIN BOUND HAEM by negative feedback
What is the half life of ALA synthase?
only 1 to 3 hours
Describe how haem and globin synthesis is physiologically regulated.
- haem inhibits activity of ALA-synthase
- haem diminishes transport of ALA-synthase from cytoplasm to mitochondria after it is made
- haem represses the production of ALA-synthase by regulating gene transcription
- haem stimulates globin synthesis to make sure that free haem remains low
What is important in balancing haemoglobin production?
- inhibiting ALA-synthase
- stimulating globin synthesis
What does ALA Dehydratase do? Where is it located?
- part of the synthesis of haem
- second enzyme involved
- cytoplasmic enzyme
- converts 2x ALAL molecules to Porphobilinogen (PBG)
What structural component does ALA Dehydratase contain? What may this lead to?
- it contains suphydryl groups
- it is sensitive to inhibition by lead (Pb2+) and other heavy metals
- – this results in high ALA synthase enzyme and symptoms of lead poisoning
What are the 3 important enzymes associated with the synthesis of haem in the liver?
[1] ALA Synthase
[2] ALA Dehydratase
[3] Uroprophyrinogen Synthase I (Hyroxymethybilane Synthase/PBG Deaminase) + UP-Cosynthase
What is the overall steps in the formation of haem?
[1] decarboxylation of acetate + propionate side groups to methyl + vinyl groups
[2] transfer into mitochondria
[3] chelation of iron
What is Porphyrias?
a group of metabolic disorders caused by partial defects in one of the haem biosynthetic enzymes
- leads to an overall reduction in haem synthesis
What happens in porphyrias?
- low haem synthesis
- accumulation of toxic intermediate products!!
- less haem means increased production to try and increase haem (positive feedback - leads to more toxic intermediates)
- can be photosensitive or non-photosensitive
What happens if there is a complete deficiency in haem?
- it would be fatal
- no oxygen
What is Acute Intermittent Porphyria (AIP)? What are the clinical manifestions due to?
- defect in uroporphyrinogen synthase I (hydroxymethylbilane synthase/PBG deaminase)
- – 50% reduction in enzyme activity
- – 90% with genetic trait never present :(
- haem synthetic pathway terminated early
- accumulation of ALA + PBG (clinical manifestations)
What are the acute attacks of Acute Intermittent Porphyria (AIP) precipitated by?
- induction of haem protein cytochrome P450 synthesis
- – slide 39
What is the treatment of Acute Intermiitent Porphyria (AIP)?
HAEMATIN - derived from haem (haem hydroxide) or Haemin
- it represses ALA synthase
What is the cause and features of Porphyria Cutanea Tarda (PCT)?
Cause:
- deficiency in uroporphyrinogen decarboxylase
Features:
- itching
- erythema
- blistering
What is the consequences of Porphyria Cutanea Tarda (PCT)?
- acccumulation of porphyrins
- accumulation of porphyrinogens (non-enzymatically converted to porphyrin)
note: photo-excited by sunlight, causing cellular damage
