Case 5

Question 1

Describe what happens in the absorptive state?

Answer 1

• Glucose is absorbed by the liver via GLUT2 receptors
• When glucose is abundant glucokinase works to change glucose into glucose 6 - phosphate
• High levels of glucose-6 - phosphate promotes glycogenesis forming of glycogen
• High levels of glucose-6-phosphate promote production of NADPH in the PPP
• Glucose-6-phosphate is used for glycolysis which is promoted by a high insulin/glucagon ratio
• Surplus carbohydrates from a meal are converted to acetyl-CoA and then channelled into fatty acid synthesis
• high ATP inhibits isocitrate dehydrogenase, leading to an accumulation of critrate in mitochondriart and export to the cytoplasm
• ATP-citrate lyase restores acetyl-CoA in the cytoplasm and ACC is activated by dephosphorylation and by citrate
• TAG synthesis is promoted by high availability of fatty acyl-CoA both from de novo fatty acid biosynthesis and from dietary fats
• Surplus amino acis are recycled, redistribtued or degraded into pyruvate, TCA cycle intermediates or acetyl coA
• Branched - chain amino acids are only used by muscle

Question 2

What are the end products of glycolysis

• Under aerobic conditions
• under anaerobic conditions

Answer 2

• Aerobic conditions - pyruvate
• Anaerobic conditions - lactate e.g. in muscles

Question 3

What are the functions of the following receptors:

GLUT2

GLUT4

Answer 3

• GLUT2 - liver
• GLUT4 - adipose tissue
• Facilitate diffusion of glucose into cells, they are on the cell membrane

Question 4

When glucose is taken up by the liver it is phosphorylated, descrie this process and name all the enzymes involved.

Answer 4

• Glucose is phosphorylated by an ATP molecule to form glucose-6-phosphate
• glucose-6-phosphate is trapped within the cell because it cannot cross the membrane spontaneously
• this reaction is catalysed by a hexokinase enzyme specifically hexokinase IV/glucokinase which has a higher capacity to trap glucose in the liver but only when glucose concentrations are high after a meal

Question 5

What is the pyruvate dehydrogenase complex?

Answer 5

Pyruvate is shuttled into mitcochondria with the help of a dedicated transporter

• The PDH complex is a group of enzymes copies of three enzymes E1,E2,E3
• The PDH is inactivated by PDH kinase which is activated by high ATP/ADP and high NADH/NAD+ but inactivated by pyruvate
• The complex needs no fewer than 5 cofactors some derived from vitamins
  
  • Thiamine - PP (B₁)
  • Lipoic acid
  • Co-enzymes A from pantothenate B₅
  • FAD from riboflavin B₂
  • NAD from nicotinamide B₃

Question 6

What is the TCA cycle

Answer 6

• Central metabolite roundabout with multiple entry points, several of the intermediates are involved in gluconeogenesis, amino acid and heme metabolism
• The oxidative catabolism of carbohydrates, lipids and amino acids came togethere here
• All TCA cycle reactions happen in mitochondria and require oxygen to recycle to the reduced co-enzymes NADH + H⁺ and FADH₂
• Provides full oxidation of acetyl- CoA to 2CO₂
• Generates reducing agents which in the ETC generate 29 ATP per glucose molecule from PDH 22 from cycle and 2 GTP

Question 7

What are excess carbohydrates or proteins in excess of the body’s needs converted to

Answer 7

• Converted to fatty acids by the liver
• Stored as fats (triacyglycerol in adipocytes

Question 8

Explain the process of using acetyl CoA to make Fatty acids

Answer 8

• Acetly-CoA is made in the mitochondria and cannot cross the membrane a shuttle is needed
• It cannot be used to make glucose it can be used to make fatty acids in the cytoplasm or go through the TCA cycle to produce energy
• ACC is used in the well fed state to make fatty acids, chain elongated from 2C to 16C
• Insulin regulates promotes making of fatty acids, regulates transcription of this enzyme
• Fatty acetyl CoA is the end product and leads to feedback inhibition stopping the first step of the cycle when made

Question 9

Regarding the beta oxidation (catabolism of fatty acids) how much ATP, FADH₂, NADH, Acetyl-CoA are produced per 2 carbon molecule.

Answer 9

• FADH₂
  
  • ​2 ATP
• NADH
  
  • 3 ATP
• Acetyl CoA
  
  • 12 ATP

Question 10

What is ketoacidosis

Answer 10

• Overproduction of ketone bodies acidifying the blood

Question 11

What does the body use for an emergency fuel

Answer 11

• Ketone bodies
• Produced by the liber to preserve glucose, the liver itself cannot use ketone bodies, it releases them into the blood for peripheral tissues
• During starvation the ability of the liver to oxidise fatty acids released from adipocytes may be limited

Question 12

What happens to excess amino acids

Answer 12

• Excess amino acids are degraded and generated nitrogen is excreted as urea
• in peripheral tissues excess ammonia is converted to glutamaine and shuttled to the liver

Question 13

Explain amino acid metabolism

Answer 13

• Most amino acids can be used in gluconeogenesis (glucogenic) but some are partially or fully ketogenic - they can form acetyl-CoA or acetoacetate
• Amino group is turned into a ketone group turning the molecule into an alpha-ketoacid which can be used in the TCA cycle, the breakdown of amino acids can be used in gluconeogenesis
• The amino group is transfered to an alpha ketoglutarate in a transmaninase reaction
• glutamate is a carrier of amine groups

Question 14

Which transmaninase enzyme is more indicative of liver damage and why?

Answer 14

• ALT is more indicative of liver damage but serum AST is more sensitive because the liver contians larger amounts of AST than ALT

Question 15

How does ALT work?

Answer 15

• Alanine transaminase
• Turns alanine into an alpha ketoacid which is used for TCA
• Removes the Alpha amine group from alanine and transfers it to glutamate

Question 16

How does AST work?

Answer 16

• Aspartate transaminase
• Removes the Amine group from glutamate and gives it to oxaloacetate to form aspartate
• Aspartae feeds into the urea cycle

Question 17

How is ammonia delivered to the liver via the alanine - glucose shuttle

Answer 17

• Alanine from the muscle delivers NH₃ via ALT
• Resulting pyruvate goes into gluconeogenesis
• Glucose is returned to the muscle

Question 18

What are the functions of the liver

Answer 18

• Phagocytosis - of particles by Kupffer clles
• Degradation of endogenous compounds and xenobiotics (drugs and toxins)
• Activation and excretion of hormones
• Excretion of lipophilic waste products - bile products
• Secretion of emulsifiers - bile products
• Storage of carbohydrates, lipids, vitamins
• Synthesis of plasma proteins, glucose, ketone bodies, cholesterol, fatty acids and amino acids

Question 19

What occurs in zone I of hepatocytes

Answer 19

• Peiportal
• Amino acid catabolism
• Gluconeogenesis
• Cholesterol synthesis

Question 20

What occurs in zone III of hepatocytes

Answer 20

• Lipid synthesis
• ketogenesis
• glutamine synthesis
• drug metabolism

Question 21

What are the functions of bile?

Answer 21

• Excretion of waste products (those not easily excreted by the kidneys)
• Excretion of hormones
• Excretion of drugs and other xenobiotics (foreign to the body)
• Secretion of bile acids/salt to aid intestinal lipid digestion and absorption
• Secretion of electrolytes and water as a vehicle

Question 22

Describe the synthesis of bile acids/ salts

Answer 22

• Syntehesised from cholesterol which is produced by the liver
• From cholesterol it forms primary bile acids which are weakly ionised, they remain in a protonated state
• Conjugation with:
  
  • Taurine
  • Glycine
  • Sulphate
  • Gluronate
• Makes them more water soluble and charged hence (bile salts)
• Dehydroxylation by bacteria in the terminal ileum and colon recycled back into liver

Question 23

Explain the apical secretion of bile salts

Answer 23

• Unconjugated and conjugated bile salts are secreted via:
  
  • Bile export pump (BSEP)
  • Multidrug resistance associated protein 2 (MRP2)
  • Both are ABC transporters

Question 24

What are ABC transporters?

Answer 24

• ATP binding casette transporters
• Huge family pumps using ATP hydrolysis to import or export wide range of substrates
• Alternating access mechanisms, powered by ATP hydrolysis

Question 25

Explain how bile acids and salts are reabsorbed in the SI

Answer 25

* Slow, passive reabsorption of unconjugated bile salts along the intestines * Active uptake of conjugated bile salts in the terminal ileum via sodium - bile salt co transport and organic solute transporter

Question 26

Describe the basolateral uptake of bile acids/salts

Answer 26

* Uptake of recycled bile salts via: * Co-transport with sodium via sodium taurocholate co-transporting peptide (NTCP) * Exchange with chloride via organic anion transporting peptide (OATP) * Also simple diffusion of unconjugated, neutral bile salts

Question 27

Explain how bilirubin is formed and excreted!

Answer 27

* Breakdown of haem to bilirubin following phagocytosis * Carried by albumin to the liver (not water soluble) taken up via OATP * Conjugation with glucuronate in ER and secretion via MRP2 * Intestinal bacteria deconjugate bilirubin and convert it to urobilinogen (colourless) * Some reabsorbed and excreted as urobilin (yellow) via kidney * Some further converted to stercobilin (brown) in colour