Liver Function Flashcards
What are the features of sinusoidal capillaries?
DAN
→ large intracellular gaps
→ allowing movement of proteins and cells across endothelial lining
→ which allows transport between blood and hepatocytes (via space of Disse)
How are hepatocytes specialised to to exchange solute between space of Disse and bile canaliculi?
DAN
→ Hepatocytes contain microvilli to increase SA for exhange from blood
→ they have special transporters that uptake, metabolise and excrete range of solutes:
NTCP → bile acid transporter
OST → organic solute transporter
MATE1 → organic cation transporter
BSEP → bile salt export pump
BCRP → drug transporter
How are lipids transported in body?
DAN
→ dietry fats and lipids get put into chylomicrons
→ which are hydrolyzed by lipoprotein lipase (LPL) to triglyerides when they touch endothelial walls
→ to release FA and glycerol to be stored in adipocytes of skeletal muscle
→ the remaining chylomicron remnants bind to endothelial cells in liver sinusoids
→ the apolipoprotein-E on surface of chylomicron remnants, which trigger clearance of plasma liproteins.
How is cholesterol metabolised?
DAN
→ liver secretes very-low density lipids (VLDL) into blood - which are converted to IDL
→ IDL can then be taken up by liver to make more VLDL or stays in circulation where it is converted to cholesterol-rich LDL
→ LDL is taken up by LDL-R on hepatocytes via internalisation un clathrin-coated pits
→ into endosome where vesicles fuse with lysosomes
→ in the lysosomes, HMG-CoA reductase degrades LDL to mevalonate - which then converted to free cholesterol in cytoplasm.
→ Statins will inhbit HMG-CoA
How is protein metabolism?
DAN
Transamination:
→ AA converted to keto acids by aminotransferase (ALT,AST)
→ and in a side reaction the NH2(amine group) is removed from AA
→ and incorparted into α-ketogutaric acid to form glutamate
Deamination:
→ Glutamate dehydrogenase
→ will convert glutamate back into α-ketogutaric acid and ammonia
Urea Cycle:
→ occurs in liver mitochondria
→ where ammonia is converted to carbamyle phosphatase
→ via carbomyl phosphatase synthase (require ATP).
Carbamyle phosphatase + orthinine = Citrilline
Citrilline → Aspartate → Arginine.
Arginine is then converted back into Orthinine but as a by-product. Urea is formed and excreted into blood.
How can ketoacidosis occur?
DAN
→ during starving/fasting states, lack of insulin or unresponsiveness insulin-dependent cells to insulin
→ means only glucagon dominates causing lots of reactions including lipolysis → as a result of lipolysis reactions
→ lots of Acely-CoA is made, which undergoes ketogenesis to form ketone bodies such as acetate and β-hydroxybutyrate
→ these then go into blood stream, increase H+ ion concentration of plasma → causing decrease pH
→ causing metabolic acidosis, which causes vomitting, increase urine output (dehydration) and fall into coma
What is bilirubin metabolism?
DAN
Breakdown of RBC:
→ Globin component broken down into AA
→ Heme component broken down into iron (taken to liver) and protoporphyrin
→ Heme is converted to Unconjugated Bilirubin (Biliverdin) and bound to albumin to be taken to liver
→ Hepatocytes convert Biliverdin to Conjugated Bilirubin via Uridine Glucuronyl Transferase (UGT)
→ UGT is stored in Bile Canaliculi
→ Intestinal bacteria convert Conjugated Bilirubin to Urobilinogen
→ Urobilinogen is then either oxidised to:
Stercobilin (brown colour of faeces) or
Urobilin (yellow of urine)
Alcohol metabolism
DAN
→ ethanol metabolised via alcohol dehydrogenase, cytochrome P-450 (particularly CYP2E1 isoform) isoenzymes or catalase
→ to form acetaldehyde
→ which is converted in mitochondria to ALDH and Acetic acid
Effects of alcohol metabolism
DAN
→ Alcohol dehydrogenase uses up NAD+
→ therefore increases NADH
→ NAD+ is depleted so less hepatic fatty acid oxidation occurs
→ which leads to fat accumulation in liver
Acetaldehyde toxicitiy
→ CYP2E1 produces ROS and lipid peroxidation causing cell damage
What is liver cirrhosis
DAN
→ triggers stellate cells to assume myofibroblast phenotype
→ causing them to deposit collagen in space of Disse
→ causing compression of sinusoidal capillaries
→ causing increase blood flow resistance through sinusoids to hepatic vein
→ causing portal hypertension
→ this then causes build up of pressure in splanchnic circulation
→ triggering NO release
→ vasodilates splanchnic arterioles → causing great blood vol in splanchnic circulation
→ so less blood reaches IVC
→ decrease MAP detected by baroreceptors
→ causing increase SNS activity in kidneys
→ increasing Na+ reabsorbtion and activates RAAS
→ RAAS increases blood vol and thirst
→ this increases blood volume
→ so can handle large scale water loss to peritoneal cavity → ASCITES
→ deposition of collagen blocks fenestrations in sinusoidal capillaries
→ so albumin cannot move into circulation
→ causing hypoalbminemia
→ this increases fluid filtration across hepatic and intestinal cappilaries into peritoneal space
→ causing increase fluid vol
→ this causes decrease blood vol then decrease MAP
→ decrease siusoidal and intestinal pressure
Morphology of cirrhosis
DAN
→ characterized by tansformation of liver
→ into regenrative parenchymal nodules
→ surrounded by fiborus bands
Where does the liver receive blood from and where does it go after?
→ liver is the largest organ and receives blood from the gastrointestinal tract
→ via the hepatic portal vein
→ the liver acts as an interface between the bloodstream and the gastrointestinal tract
Inputs:
→ hepatic artery (O2 rich)
→ hepatic portal vein (nutrient rich)
Outputs:
→ bile duct
→ hepatic vein —> IVC
Key features
→ low blood pressure
→ low vascular resistance
Liver function (4)
→ filters blood
→ stores and releases metabolites
→ production of bile and coagulation factors
→ metabolises vitamins and hormones
Hepatic lobules
Apical side of the hepatocyte
→ faces the Bile Canaliculi
Basolateral side of the hepatocyte
→ faces space of Disse
Consist of:
→ central vein
→ 6x portal triad areas
→ sinusoids
→ hepatocytes
→ bile caniculi
→ Space of Disse
→ cords
Split into zones 1-3:
→ zone 1 is closes to portal triad
→ zone 3 is closest to central vein
Kupffer cells
→ population of fixed macrophages
→ part of reticuloendothelial system
→ help to act as the final component of the gut barrier to pathogens taken up via the gastrointestinal system
→ as well as helping to remove ageing erythrocytes and particulate matter from blood
Hepatic stellate cells
At rest:
→ responsible for storing vitamin A
→ in large lipid droplets inside cell
Upon activation:
→ produce collagen and ECM components
Sinusoidal capillaries
→ large intercellular gaps that allow free movement of proteins and cells across the endothelial lining
→ allowing for effective transport between blood and hepatocytes via the space of Disse
→ liver and spleen have capillaries with incomplete basement membranes and intercellular gaps
→ means a much higher Kf
Hepatocytes
→ Secretory epithelial cells
→ specialised for exchanging solutes between the space of Disse and the bile canaliculi
→ have microvilli to increase SA for exchange from blood
→ able to uptake, metabolise and excrete a wide range of solutes using both multidrug-resistance-associated proteins (MRP) and organic anion transporters (OAT)
Lipid transport
- lipoprotein synthesis, secretion and reuptake
- chylomicron processing
- bile salt production
→ Dietary fats are broken down into fat droplets
→ then broken down into fatty acids, glycerol and cholesterol
→ these are packaged into chylomicrons and travel in the lymphatic system; until they are transformed into VLDL and HDL to travel in systemic circulation
→ travel in the blood to muscle and adipocytes
→ remnant chylomicrons and extra LDL are taken to the liver where they are excreted as bile salts back into the digestive tract
Cholesterol metabolism
Happens in the liver:
→ Acetyl CoA
→ HMG-CoA
→ mevalonate
→ cholesterol
→ VLDL
→ travels in the blood
Or
→ Acetyl CoA
→ HMG-CoA
→ mevalonate
→ cholesterol
→ excreted into bile as a primary bile acid (cholic acid and chenodeoxycholic acid)
→ bacteria converts them into secondary bile acids (deoxycholic acid, lithocholic acid)
→ enterohepatic circulation
Statins block mevalonate production
Protein metabolism
Amino acids:
1) deamination to urea
2) Transamination to non-essential fatty acids
3) Gluconeogenesis
4) Protein synthesis - metabolism: albumin, lipoproteins
Inflammation:
→ CRP
→ complement C3
Endocrine:
→ angiotensin
→ albumin
→ plasma binding proteins
Blood coagulation:
→ prothrombin
→ factor VII
→ factor IX
→ factor X
→ fibrinogen
→ plasminogen
Coagulation cascade
→ activated platelets within the thrombus start to express phosphatidylserine on their external face of their plasma membrane
→ circulating tissue factor an other clotting factors bind to the platelet plasma membrane in a calcium-dependent manner. This helps localised all the components of the coagulation cascade to the platelet surface making its catalysis more effective
→ this also helps limit the activation of thrombin to the surface of the platelet aggregate preventing excessive blood clotting
→ thrombin produced cleaves fibrinogen to fibrin
→ fibrin monomers spontaneously polymerise to form a gel
→ cross linking of fibrin by factor XIIIa then creates a strong, insoluble fibrin mesh which prevents the clot from being washed away by the flowing blood
Carbohydrate metabolism - glucose buffer function of liver
1) regulation of blood glucose by glycogen synthesis and breakdown
2) gluconeogenesis
3) conversion of carbohydrate and proteins into fatty acid and triglyceride
Controlled by:
→ insulin
→ glucagon
→ circulating catecholamines
→ sympathetic nervous system
Example:
→ Low blood glucose
→ glucagon glucocorticoids increases glyconeolysis
→ increases gluconeogenesis
→ decrease in glycogen storage as there has been glucose production
High blood glucose
→ insulin increase glycogen store
→ less gluconeogenesis
→ less glycogenolysis as glucose has been uptaken and stored
Insulin
Insulin promotes anabolism and storage
Skeletal muscle:
→ increase glucose uptake (exocytosis insertion of GLUT4)
→ increase glycogen storage (transcription of hexokinase and glycogen synthase)
→ promotes protein production
→ promotes glycolysis
Liver:
→ increase glycogen storage (transcription of hexoinase and glycogen synthase)
→ promotes glycolysis
→ inhibits gluconeogenesis (inhibiting PEPCK, fructose 1,6 biphosphate and glucose-6-phosphate)
→ promotes the synthesis and storage of fats
→ promotes protein production
Adipocytes:
→ increase glucose uptake (exocytotoic insertion on GLUT4)
→ increase glycogen storage (transcription of hexoinase and glycogen synthase)
→ promotes triglyceride production (promotes esterification and inhibits hormone-sensitive lipase)
