Liver Function & Fed/Fasted Metabolism

Liver Function & Fed/Fasted Metabolism

1. METABOLISM FED/FASTED

   • GLUCONEOGENESIS (GNG)
     • GNG is almost the reverse of GLYCOLYSIS but uses enzymes (in blue) needed due to large free energy change
       • NB. Enzymes are differentially regulated to prevent futile cycling
       • GNG consumes ATP and GTP - is energetically expensive but NEEDED
     • WHY? Brain has no reserves so we ALWAYS need a glucose supply. Glycogen reserves in liver aren't enough. SO we synthesise glucose from pyruvate, glycerol & AAs = GNG IN LIVER. Needed in STARVATION or VIGOROUS EXERCISE.
       • Animals can't produce glucose from fatty acids but plants can (why seeds are full of fat)
     • Any compound that can form PYRUVATE/OXALOACETATE can initiate GNG
       • The path from PYRUVATE to PHOSPHOENOLPYRUVATE (PEP) is via OXALOACETATE, an intermediate of the citric acid cycle
       • TRAVERSES MITOCHONDRIA. Inner mitochon membrane permeable to malate, PEP & pyruvate.
         • OVERALL: 2xPyruvate + 4xATP + 2xGTP + 2xNADH + 2xH+ + 4xH2O = 1xGlucose + 4xADP + 2xGDP + 2xNAD+ + 6xPi
           • OVERALL GNG COSTS (per glucose): 4xATP, 2xNADH 2xGTP
   • REGULATION OF FED <> FASTED STATES
     • Proteins
       • How alter rates of biochemical reactions? See diagram below right
         • Half-life of proteins varies between tissues eg. muscle is 10days!
     • Substrate Conc
       • Feedback Inhibition
         • Often, products of a metabolic pathway, directly/indirectly reduce rate
           • eg. glycolysis: HEXOKINASE inhibited by GLUCOSE-6-PHOSPHATE. PHOSPHOFRUCTOKINASE inhibited by ATP.
       • Many enzymes have a Km that is near/greater than the conc of their substrate.
     • ATP and AMP
       • AMP = Adenosine MONOphosphate
         • ATP > Pi + ADP
           • 2xADP >(adenylate kinase)> AMP + ATP
             • Presence of AMP indicates usage of ATP
       • Both act on individual enzymes and whole organism via AMP-activated Protein Kinase (AMPK)
         • eg. GNG and Glycolysis - ADP & ATP ALLOSTERICALLY regulate PFK & FBPase (feedback control). PFK also activated by insulin, inhibited by glucagon.
         • 1) AMP activates AMPK (via leptin & adiponectin in adipose tissue, and SNS)
           • 2) AMPK regulates metabolic proteins by phosphorylating them (Opt. 9)
             • AMPK shifts metabolism away from energy-consuming synthetic pathways > ACTS TO RAISE [ATP]
               • Extrahepatic tissues: stimulates use of fatty acids for fuel
               • Liver: stimulates GNG, slows synthetic pathways
               • Brain: stimulates feeding for fuel
     • Acetyl CoA > Fate of Pyruvate
   • FATTY ACIDS
     • 1/3 of our energy needs comes from dietary triacylglycerols (TAGs)
     • Fats most energy efficient for storage: highly reduced & bind little H2O
       • eg. hibernating bears
     • Oxidation provides energy for HEART, LIVER, KIDNEYS & RESTING MUSCLE
     • 1) Absorbed in S. INTESTINE. 2) Bile > mixed micelles. 3) Lipase breaks fatty acids > TAGs. 4) TAGs + cholesterol + apolipoproteins > chylomicrons. 5) Travel via lymphatic system/blood > tissues (myocyte or adipocyte)
       • Motility, Digestion & Absorption
       • 6) Lipoprotein lipase converts TAGs back to fatty acids and glycerol
         • 7) fatty acids OXIDISED as fuel
           • OXIDATION...
             • Transported into mitochondria via carnitine shuttle
               • Stage 1) β oxidation: fatty acids are oxidised 2 carbons at a time and combine with CoA to form ACETYL-CoA, and high energy e's in the form of NADH and FADH2.
                 • Stage 2) ACETYL-CoA enters citric acid cycle (ie. Step 3 of resp) > NADH and FADH2.
                   • Stage 3) the high energy e's in NADH and FADH2 synthesise ATP in oxidative phosphorylation (electron transport chain! ie. Step 4 of resp)
                 • Fatty acids > acetyl-CoA - explains KETOGENESIS...
                   • When ACETYL-CoA from fatty acids (and some AAs) are in excess > converted into ketone bodies in LIVER MITOCHONDRIA > EXPORTED to tissues
                     • (reserves oxaloacetate for GNG)
                       • NB. GNG requires oxaloacetate. This TAKES PREFERENCE over acetyl-CoA's entry into citric acid cycle (by ketones)
                     • 3 types of ketone bodies:
                       • Acetone - exhaled
                       • Acetoacetate & β-hydroxybutyrate - FUEL for extrahepatic tissues by conversion back to ACETYL-CoA (>entry into citric acid cycle)
                         • (Heart prefers acetoacetate to glucose)
                         • Acetoacetate detected on urine dipstick
                     • REMEMBER THIS: "Ketone bodies are a form of mobile acetyl-CoA (which can enter Citric Acid Cycle)"
                 • This Acetyl Co-A can EITHER: enter CITRIC ACID CYCLE (Resp continues as normal) OR (when in excess) is converted into KETONE BODIES in liver (reserves oxaloacetate for GNG)
         • 7) or reesterified for storage
   • FED/FASTED OVERVIEW
     • When FASTING: Liver is PRINCIPAL SOURCE of GLUCOSE for BRAIN
     • When FED:
       • ARROWS:
         • GLUCOSE
           • AMINO ACIDS
             • LIPIDS
               • UREA
                 • KETONE BODIES
     • When PROLONGED FASTING / DM Type II:
       • OXALOACETATE preferentially used for GNG to maintain BLOOD GLUCOSE. This slows the citric acid cycle in liver, so enhances formation of KETONE BODIES, releasing CoA for β oxidation to continue. Ketone bodies used as fuel for extrahepatic tissues.
   • VITAMINS & MINERALS
     • Vitamins = organic molecules that cannot be synthesised > dietary. Categorised according to solubility in fat (or H2O if Vit B/C). Act as COENZYMES or ANTIOXIDANTS.
       • Vitamins A, B (complexes), C, D, E, K
         • *See lecture slides for function of each
     • Minerals = Excreted in urine/sweat so have to be replaced.
       • Ca, Na, K, Mg
     • Trace Elements eg. Fe, Zn, Cu
   • TISSUE PROFILES
     • BRAIN = no fuel reserve. GLUCOSE is the only fuel, apart from KETONES in prolonged starvation. Consumes 120g glucose/day (60% of entire body at rest). Glucose below ~2mM > hypoglycaemic coma > death.
     • MUSCLE = uses GLUCOSE, FATTY ACIDS, KETONE BODIES. When contracting, glycolysis exceeds citric acid cycle so pyruvate > lactate (back to glucose by liver). When resting, FATTY ACIDS are used (meets 85% of energy needs)
     • HEART = almost all AEROBICALLY. No glycogen reserves. Uses mainly FATTY ACIDS, or KETONE BODIES or LACTATE [or ACETOACETATE (ketone body produced by liver) over glucose].
     • LIVER = FATTY ACIDS. Fatty acid synthesis. Removes 2/3s of glucose from blood and monosaccharides. FED state: glucose 6-phosphate > acetyl CoA > fatty acids, cholesterol, bile salts. FASTING state: fatty acids > acetyl CoA > ketone bodies.
   • GLYCOGEN SYNTHESIS / GLYCOGENOLYSIS
     • Glucose<>Glycogen. Glycogen rapidly synthesised/degraded according to need.
       • GLYCOGEN SYNTHASE (LIVER) activated by GLUCOSE & GLUCOSE 6-PHOSPHATE
       • GLYCOGEN PHOSPHORYLASE (MUSCLE) activated by AMP and Ca2+. (Converts glycogen into glucose 1-phosphate)
         • Both enzymes controlled by INSULIN, GLUCAGON, ADRENALIN.

2. BILIARY CIRCULATION

   • Bilirubin metabolism PROBLEMS
     • If too much bilirubin before liver = ^unconjugated bilirubin = PREHEPATIC JAUNDICE eg. haemolytic anaemia, spherocytosis of RBCs, haemolysis
       • High bilirubin = JAUNDICE. Bilirubin is UV mobile (broken up/dispersed when exposed to UV). SEVERE jaundice = yellow sclera. MILD jaundice/ANAEMIA = white where UV shines on eye (bilirubin broken up) BUT yellow under eyelids
         • GILBERT'S SYNDROME = ^isolated bilirubin (stressful triggers eg. dehydration) Can be normal and go down.
     • Also POST-HEPATIC conjugated bilirubin stopped from getting from liver to gut eg. by GALL STONES.
       • Excess conjugated bilirubin in liver No urobilinogen in faeces = fats not emulsified > PALE/FLOATING STOOL Bilirubin goes into kidneys instead > DARK URINE
     • Blood tests
       • LIVER PROFILE: bilirubin ALT ALP albumin
         • Bilirubin conjugated or not? Work out location of problem
         • Liver isoenzyme of alkaline phosphatase found in biliary ducts. RAISED ALP in lover suggests cholestasis (blockage of biliary system)
         • NB. RAISED ALP also in BONE DISEASE and PREGNANCY (produced by placenta)
   • BILE SALTS are synthesised from cholesterol. Emulsify lipids before intestinal absorption. Made in liver and stored in gall bladder.
     • Cholesterol > Bile acids > Cholic acid
     • ENTEROHEPATIC CIRCULATION
       • Bile salts recirculated several times per day - EITHER reabsorbed as UROBILINOGEN or lost as STERCOBILIN
       • Also elimination of drugs
         • DETOXIFICATION

3. SYNTHETIC FUNCTION (albumin, clotting factors, α and β globulins)

   • ALBUMEN
     • Makes up 50% of plasma proteins (ref range 35-45g/L). Main factor in ONCOTIC PRESSURE.
     • Carrier protein for CALCIUM and BILIRUBIN (ie. can calculate corrected Ca2+ level)
     • Causes of HYPOalbuminaemia: liver disease, nephrotic syndrome, malnutrition, burns
       • Low albumin increases osmotic pressure of ECF > PERIPHERAL OEDEMA
   • CLOTTING FACTORS (ABC case Yr 2)
     • synthesised in liver (look at ALT or AST for clotting ability when giving transplant)
     • Cholestasis: malabsorption of Vit K
     • Low platelets - Impaired thrombopoietin synthesis (makes platelets)

4. METABOLISM (Carbohydrates, proteins, lipids)

   • Lipids
     • (see Chest Pain case Yr2) - affects cholesterol & triglyceride lipid levels
   • Proteins
     • Transamination (break down proteins into AA's to produce energy) *SEE N2 lecture in Urinary
       • Urea cycle
         • Liver damage = problems with urea cycle > HYPERAMMONAEMIA > brain problems (ENCEPHALOPATHIC)
           • from GENETIC DISEASES that affect enzymes (baby will have ^NH3 - need low protein diet and no fasting as will start digesting own muscles for protein)
           • from ALCOHOLIC liver damage
       • AMINOTRANSFERASES should be IN HEPATOCYTES so sign of liver damage if in bloodstream
         • Clinically, we use ALT (Alanine transferase) which is SENSITIVE and SPECIFIC to liver (>50 = hepatocellular damage)
           • Perviously used AST (Aspartate transaminase) but also produced with heart damage. Troponin now marker for heart damage.
   • Carbohydrates
     • altruistic organ - RELEASES GLUCOSE into blood for rest of body (unlike skeletal muscle which makes own glucose)
       • Relationship between LIVER & PANCREAS
       • Glucose level when fasting = 4mmol. If continue to fast - glucose level kept constant by breaking down glycogen or muscles
         • See RHS of mind map
     • GLUCONEOGENESIS
     • GLYCOGEN STORAGE

5. STRUCTURE

   • Hepatic portal system
     • build up of blood > block > chronic liver disease
   • Microanatomy

6. LIVER DISEASE SUMMARY

Imagens e arquivos do mapa