metabolic functions of liver

what is the role of the hepatic artery

supplies oxygen rich blood from heart to liver, provides 20-30% of blood to liver

what is the role of the portal vein

supplies nutrient rich blood from the digestive tract, supplies 70-80% blood to liver

where do the portal vein and hepatic artery arise from

portal - GI tract

hepatic artery arise- aorta

what are the main cells of the liver

hepatocytes, kupffer cells and macrophages

what occurs in zone 1 of the liver lobule

oxidative functions

what occurs in zone 3 of the liver lobule

metabolic processes requiring lower oxygen

where is zone 1 of liver lobule located

closer to the afferent arteriole

list roles of zone 1

• Respiratory chain

 

• Citric acid cycle

 

• Fatty acid oxidation

 

• Gluconeogenesis

 

• Urea synthesis

 

• Production and bile excretion

where is zone 2 located in liver lobule

ill defined, intermediate area

where is zone 3 of the liver lobule located

closer to the terminal hepatic veins

list the roles of zone 3 in the liver lobules

• Glucolysis

 

• Glutamine synthesis

 

• Xenobiotic metabolism

what is the other names of zone 1 and zone 3

zone 1 = peri portal

zone 3 = perivenular

what is the whole body energy metabolism driven by

the need to ensure adequate glucose supply for the brain and creation of ATP in cells

what is the energy metabolism dependant on

adequate intake and on the ability to store glucose between meals

what organ is primarily responsible for energy metabolism

the liver

what is glycolysis

a set of reactions that converts glucose into pyruvate or lactate

what is the energy released in glycolysis used for

used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH).

what does pyruvate become

an intermediate in the krebs cycle or can be converted into acetyl coa which enters the krebs cycle to produce energy for the cell

what is gluconeogenesis

hepatocytes can synthesise glucose from non carbohydrates courses

what non carbohydrate sources can be used in gluconeogenesis

lactate

glycerol

amino acid

when is gluconeogenesis stimulated

during fasting

what hormones stimulate gluconeogenesis

glucagon, growth hormone and cortisol

what are blood glucose levels like following a meal

high

what hormone is stimulated in a fed state

insulin by beta cells of pancreas

what does insulin promote

uptake of glucose by hepatocytes (and muscle), where it is stored as glycogen if not immediately needed

what does a fall in plasma glucode stimulate

glucagon release

what do glycogen stores amount to, when are they readily mobilised

600cals of more

readily mobilised when plasma glucose levels start to fall, between meals

what does glucagon stimulate

breakdown of glycogen to glucose (glycogenolysis), which is released into blood for use by other tissues

what does adrenaline stimulate in exercise

glycogenolysis

what is glycogenolysis

Breakdown of glycogen to glucose-1-phosphate plus glycogen(n-1).

what are glycogen branches catabolised by in glycogenolysis

sequential removal of glucose monomers by phosphorolysis by the enzyme glycogen phosphorylase.

what is glucose-1-phosphate converted to, by what

glucose-6-phosphate by phosphoglucomutase

what is lipogenesis

Hepatocytes can synthesise lipids (triglycerides) from glucose or amino acids

what are excess carbohydrates, protein and fat converted into in lipogenesis

triglycerides and stored in adipose tissue

what is lipolysis

fatty acids can be derived from triglycerides to produce ATP

what are triglycerides broken down into in lipolysis

glycerol and fatty acids

what is lipolysis catalysed by

lipases

what is lipolysis enhanced by

adrenaline and noradrenaline released during increased sympathetic tone

what inhibits lipolysis

insulin

what does lipolysis result in

glycerol and fatty acids

what does the glycerol from lipolysis enter

Glycerol enters the glycolysis/gluconeogenesis pathway and can either be converted to glucose or pyruvate, depending if ATP is high or low in the cell

what do the fatty acids of lipolysis undergo

beta oxidation in the matrix of the mitochondria producing acetyl CoA

what does acetyl coa enter

the krebs cycle

polarity of lipids, what does this cause

non polar and thus hydrophobic so they will not dissolve in water

why are lipids combined with proteins

to make them water soluble, this will create a lipoprotein

what occurs in conditions of plenty

fatty acids produced by the liver ad together with those obtained from the diet are esterified and secreted into the blood as VLDLs

where are VLDLs hydrolysed, by what

hydrolysed in adipose and muscle tissue by lipoprotein lipase to release free fatty acids and glycerol

what happens to the glycerol and fatty acids produced after esterification

glycerol will return to the liver and enter glycolysis via gluconeogenesis

fatty acids are taken up by the tissues

what happens to VLDLs when they deposit triglycerides

they become LDLs

what does LDLs transport and why

cholesterol, used in repair of cell membranes and synthesis of steroid hormones and bile salts

what happens in excessive numbers of LDL

deposit cholesterol in arteries

role of HDLs

remove excess cholesterol from cells and take it to the liver for elimination

what is ketogenesis

In conditions of starvation, the liver converts fatty acids to ketone bodies (acetoacetate and beta-hydroxybutyrate) which are released into the blood for utilisation by the CNS and muscle tissue (the liver itself cannot utilise ketone bodies)

what is the switch in ketogenesis regulated by

malonyl CoA

when is malonyl CoA concentration high

high concentrations after a meal and declines after starvation

how are proteins synthesised vs breakdown

synthesis - transcription and translation

breakdown - proteases

why is the liver especially important in protein metabolism

• It stores more proteins than other tissues

 

• Can rapidly synthesise or degrade proteins.

 

• It also can quickly synthesise and degrade amino acids, unlike most other tissues

• It produces more than 90% of circulating proteins, e.g. Albumin, lipoproteins, glycoproteins

what happens to proteins in digestion

converted to amino acids

what are amino acids oxidised for

ATP or used for body growth and repair

what are excess dietary amino acids converted to

glucose by gluconeogenesis and lipids by lipogenesis

what is protein anabolism

creating proteins by forming peptide bones between amino acids

what is a complete protein

contains adequate amounts of all essential amino acids

 

How is a non essential amino acid produced

transamination; transferring an amino group from an amino acid to pyruvuc acid to an acid in the krebs cycle

what is protein catabolism

proteins from worn out cells are broken down into amino acids

what do hepatocytes convert amino acids into

fatty acids

ketone bodies

glucose

what is produced when amino acids are oxidised

ATP

what must occur before amino acids are oxidised

deamination; their amino group must be removed

deamination in the liver results in what

this occurs in hepatocytes and produced nitrite containing amino groups

what can ammonia do

alters plasma acid base balance

what is ammonia converted to

urea

where is hepatic bile secreted by and into where

secreted by hepatocytes into bile canaliculi

what does bile contain

• Bile salts (process fat in SI)

 

• Bile pigments

 

• Cholesterol

 

• Lecithin

• Mucus

role of ductal epithelial cells

add watery, bicarbonate rich fluid

how are bile salts transported to the liver

enterohepatic circulation

how do bile salts enter the hepatocytes

sodium deposit organic anion transporter

what happens to bile salts once they are in the hepatocytes

• actively transported into bile canaliculi by an active bile salt export pump

 

• Epithelia of bile canaliculi transport sodium and bicarbonate into lumen and water follows passively

what does epithelia of bile canaliculi transport

sodium and bicarbonate into lumen and water follows

what is sodium and bicarbonate into lumen stimulated by

secretin

glucagon

gastrin

what is bile acid independant bile secretion

• Refers to secretion of water and electrolytes by hepatocytes and ductal epithelial cells

• Sodium and bicarbonate are actively secreted into the bile ducts

• Passive movement of water and chloride follows

 

what percentage of bile salts are recycled

94%

how are bile salts reabsorbed

• Reabsorbed into portal circulation in terminal ileum

what happens to bile salts which do not become secondary bile salt

excreted in faeces

what is the main regulator in regulation of bile secretion

return of bile salts in enterohepatic circulation

what happens to bile secretion following a meal

increased return via the circulation increases bile production

what happens to fluid production in bile secretion in a fed state, what mediates this

• Fluid production by the ductal epithelial cells is enhanced by secretin

• To a lesser extent also enhanced by gastrin and glucagon

where does bile excretion begin

bile canaliculi,  enters hepatic ducts, then to common  hepatic & bile duct

main component of bile excretion

bilirubin

what drugs can bile excrete

morphine and rifampicin

what is excess cholesterol excreted in

bile

what might there be an issue with in metabolic disorders of the liver

• amino acid metabolism

 

• of bile acid synthesis and metabolism

 

• of carbohydrate metabolism

 

• of bile flow and excretion

• of mitochondrial function

 

what might metabolism functions of the liver be disturbed by

• Congenital deficiency of enzymes

 

• Nutritional deficiency/excess of substrate

 

• Toxic/chemical damage to organelles

 

• Hypoxic/ischaemic insult

• Secondary to metabolic effects of disease

 

what are inherited disease causing metabolic dysfunction in the liver

• Essential product deficit

        e.g. G-6-P deficiency

        (Glycogen storage I)

 

• Precursor accumulation

        e.g. OTC deficiency

        (Hyperammonaemia)

 

• Alternative pathway activation

        e.g. Amino-acidopathy

 

• Combinations of above

how might mitochondrial damage cause liver dysfunction

• Inhibition of beta oxygenation of fatty acids

        leads to micro-vesicular steatosis

 

• Interference with oxidative phosphorylation

        leads to insufficient ATP generation

 

• Impairment of the respiratory chain

        leads to excess ROS with lipid     peroxidation

 

• Increase in permeability transition

        leads to cell death (apoptosis)

 

what are some things which can cause toxic damage to the liver

• Mitochondrial damage

        Drugs (antivirals, salicylate, valproate,         tetracycline)

        Toxins (hypoglycin, atractyloside)

 

• Endothelial damage to hepatic veins

        Drugs (cytotoxic drugs)

        Toxins (Senecio, aflatoxin, pyrrolizidine)

 

• Glutathione depletion and cell death

        Drugs (paracetamol)

        Hypoxic ischaemia

pathological manifestations of metabolic disease of the liver

• No structural abnormalities evident but severe functional disturbance

 

• Hepatocyte injury leading to apoptosis, necrosis, cirrhosis or tumors

• Storage of lipid, glycogen or other products manifesting as hepatomegaly

clinical patterns of metabolic disease involving the liver

• Newborn acute metabolic crisis

        mimics sepsis

 

• Severe vomiting and failure to thrive

 

• Recurrent episodes of vomiting and encephalopathy with acidosis

 

• Progressive disability or seizures with hepatomegaly

• Hepatomegaly with/without jaundice and failure to thrive/grow normally

what is nitrogen converted to in the liver

urea

what will stimulate bile secretion

gastrin

when does reye like syndrome present

neonatal to 3 years

what are symptoms of reye like syndrome

episodic vomiting since neonatal period and failure to thrive