POM 1

Question 1

Glycolysis

Answer 1

10 steps

Question 2

Kreb cycle

Answer 2

8 steps

Occurs in the matrix of the mitochondria

Question 3

Beri beri

Answer 3

Thiamine deficiency à thiamine is cofactor of pyruvate dehydrogenase complex

o So, deficiency of thiamine leads to Beri Beri à difficult to make acetyl CoA from pyruvate – effects on metabolism + respiration

o SYMPTOMS: Damage to peripheral nervous system, Weakness of musculature, Decreased cardiac output

o Brain particularly vulnerable as it relies heavily on glucose metabolism

Question 4

Metabolism of protein

Answer 4

Protein metabolism involves transamination reactions à amine group transferred from 1 amino acid to keto acid forming new pair of amino acid and keto acids (uses aminotransferases) – GROUP TRANSFER

· Degradation of all 20 amino acids leads to 7 molecules:

o Pyruvate

o Acetyl CoA

o Acetoacetyl CoA

o Alpha-ketoglutarate

o Succinyl CoA

o Fumarate

o Oxaloacetate

The glucogenic amino acids are so-called because their skeletons can give rise to glucose via gluconeogenesis (dashed line). Ketogenic amino acids give rise to skeletons which cannot enter gluconeogenesis but can be used to synthesis fatty acids and ketone bodies.

Question 5

Metabolism of fatty acids

Answer 5

Fatty acid metabolism produces acetyl CoA

· Fats derived from 3 main sources à (1) diet, (2) de novo synthesis in liver, (3) storage in adipose tissue

· Fats are insoluble so require bile salts to be absorbed by the gut

o Bile salts are created by the liver and stored in the gallbladder

o Bile salts aid absorption of fat and fat-soluble vitamins (2, 7, 9 and 10)

o Lack of bile salts à steatorrhea (fatty, oily stools)

Question 6

Orlistat (drug)

Answer 6

Inhibits pancreatic and gastric lipases

o Reduces fat absorption by 30% à treats obesity for up to 2 yrs

o Adverse side effects e.g. abdominal pain

Question 7

Alcohol metabolism in the liver

Answer 7

Cytoplasm
- ethanol +NAD -> acetaldehyde + NADH + H+

Mitochondria

• Acetaldehyde + NAD+ + H20 -> Acetate + NADH + H+
• Acetate + coenzyme A + ATP -> acetyl coA + AMP + PPi

Microsomal ethanol-oxidising systems (MEOS)

• Inducible
• Part of the P450 family of proteins
• Ethanol -> acetaldehyde
• uses NADPH as co-factor

Oxidation of ethanol
• Ethanol -> Acetaldehyde
- Alcohol dehydrogenase (cytosolic): reduces NAD+
- Microsomal ethanol oxidizing system (MEOS) in ER
Co-oxidise NADPH, reduces O2
[↑ in chronic alcoholics, minor otherwise]
• Acetaldehyde -> Acetate
- Acetaldehyde dehydrogenase (mitochon): reduces NAD+
- Acetate converted to acetyl CoA and fed into TCA cycle

Question 8

How ethanol metabolism results in accumulation of NADH

Answer 8

Inhibits gluconeogenesis

• inhibit conversion of lactate to pyruvate
• lactic acidosis
• hypoglycaemia

Inhibit fatty acid oxidation

• role of beta-oxidation is to generate NADH
• Conditions promote fatty acid synthesis
• ‘fatty liver’ with accumulation of TAG

Inhibit TCA cycle
-NADH regulates key steps in this cycle

Question 9

How metabolism of alcohol result in production of acetate

Answer 9

Acetate turns into acetyl-coA

BUT

• TCA cycle is inhibited by NADH accumulation
• so ketone bodies will be formed
• ketoacidosis

Question 10

How metabolism of ethanol results in accumulation of acetaldehyde

Answer 10

Very reactive compound
• Forms covalent bonds with functional groups in proteins, nucleotides and phospholipids

• Binds to glutathione, thereby reducing the antioxidant capacity of liver
– Situation is worsen by induction of MEOS
• increase utilization of NADPH, thereby reducing the ability to regenerate oxidized glutathione
• MEOS will also increase free radical formation

Question 11

Beta oxidation

Answer 11

Produces >50% of body’s energy, not in brain cells as fat acids cannot cross BBB, not in RBC as they do not hav mitochondria

o Predominates in times of fasting à when fat metabolism dominates during fasting, acetyl CoA forms ketone bodies (don’t enter TCA cycle)

o Fatty acids ultimately converted into acetyl CoA in mitochondria à used to produce ATP

o 1. Fatty acids used to generate acyl CoA (ATP à AMP) à occurs on outer mitochondrial membrane

o 2. Acyl carried across membrane to mitochondria matrix in acyl carnitine à acyl bonds back to CoA (acyl added to carnitine using carnitine acyltransferase I)

Carnitine and Acyl carnitine are moved to and from the matrix by a translocase.

o 3. Acyl CoA goes through cycle of oxidation, hydration,

oxidation and thiolysis reactions to generate acetyl CoA (beta-oxidation spiral)

o 4. Cycle repeats until finalAcyl CoA is metabolised into acetyl CoA molecules

o Acetyl CoA generated only enters TCA cycle if B oxidation and carbohydrate metabolism are balanced as oxaloacetate is needed for acetyl CoA to enter the cycle

o NET RESULT OF EACH CYCLE è 1 x Acetyl CoA, 1 x Acyl CoA (2 Cs shorter), 1 x FADH2, 1 x NADH

Question 12

Lipogenesis

Answer 12

Fatty acids are formed sequentially by decarboxylative condensation reactions involving acetyl CoA and malonyl-CoA

o Following each round of elongation, fatty acid undergoes reduction and dehydration by sequential action of ketoreductase (KR), dehydratase (DH) and enol reductase (ER) activity

o Growing fatty acyl group is linked to an acyl carrier protein (ACP)

KEY STEPS
• Acetyl CoA from glucose transported into cytosol as citrate
• Malonyl CoA formed by acetyl CoA carboxylase (ACC), requiring biotin
cofactor: committed irreversible step
• Stepwise elongation of acyl chain 2C at a time by fatty acid synthase
(FAS) (multienzyme complex + acyl carrier protein)
• Palmitate released by hydrolysis, combines with G3P to form triglycerides

Question 13

Oxidative phosphorylation

Answer 13

Occurs on the inner membrane

NADH needs to enter mitochondrial matrix to be used to regenerate NAD+

· Electrons from NADH are carried across mitochondrial membrane via shuttles (rather than NADH itself)

· Done through 2 different shuttles:

o GLYCEROL-PHOSPHATE SHUTTLE

o MALATE-ASPARTATE SHUTTLE

Question 14

Glycerol-phosphate shuttle

Answer 14

Skeletal muscle and brain

Cytosolic G3P dehydrogenase transfers electrons from NADH to DHAP (dihydroxyacetone phosphate) to generate G3P

§ Membrane bound form of same enzyme transfers electrons to FAD – these then pass on to co-enzyme Q, part of ETC

Question 15

Malate- aspartate shuttle

Answer 15

à liver, kidney, and heart

§ Also relies on cytosolic and membrane bound forms of same enzymes – aspartate transaminase and malate dehydrogenase

Aspartate glutamate) -> oxaloacetate
Oxaloacetate NAD+) -> malate
§ Transamination reaction as well as redox and group transfer

Question 16

Electron transport chain

Answer 16

Occurs in inner membrane of mitochondria

o Consists of 3 complexes and 2 mobile carriers

o COMPLEXES à NADH dehydrogenase, cytochrome b-c1, cytochrome oxidase complex

o MOBILE CARRIERS à ubiquinone, cytochrome c

o As electrons from co-enzymes pass through each complex, proton is pumped into intermembrane space

o Protons move from high to low concentration through enzyme allowing ATP to be synthesised

FADH2 produces fewer ATP as Complex I is bypassed and fewer protons are pumped into inner membrane space

Question 17

ATP

Answer 17

Produced by ATP synthase à torsional energy fixes phosphate to ADP – can be forward or reverse

o Direction of H+ flow dictates ATP synthesis vs ATP hydrolysis

o Oxidation of 1 x acetyl CoA molecule gives 3 x NADH + 1 x FADH2 + 1 x GTP = 12 ATP

o NOTE: creatine kinase acts as a buffer for ATP production during exercise à creatine phosphate buffers demands for phosphate during exercise

Question 18

Redox reaction

Answer 18

Substrate that can exist as oxidised and reduced forms = redox couple e.g. NAD+/NADH or FAD/FADH2

o +ve E’0 implies tendency to ACCEPT electrons = more OXIDISING POWER = more likely to be REDUCED

o -ve E’0 implies tendency to DONATE electrons = more REDUCING POWER = more likely to BE OXIDISED

o Transfer of electrons from one complex to another is energetically favourable

o Electrons lose energy as they progress through the chain

Question 19

Malonate

Answer 19

Closely resembles succinct explanation and acts as a competitive inhibitor of succinate dehydrogenase ->slows down the flow of electrons from succinate to ubiquinone (complex q) by inhibiting the oxidation of succinate to fumarate

Question 20

Rotenone

Answer 20

Found in roots and seeds of some plants, inhibit transfer of electrons from complex I to complex q

Question 21

Cyanide CN- and azide N3-

Answer 21

Bind with high affinity to ferric acid Fe3+ form of Haem group in cytochrome oxidase complex which blocks final step of ETC

Question 22

Oligomycin

Answer 22

Antibiotic produced by streptomyces -> inhibits oxidative phosphorylation by binding to stalk of ATP synthase and blocking the flow of protons through enzymes

Question 23

DNP

Answer 23

A proton ionophore which can shuttle protons across the inner mitochondrial membrane without passing through ATP synthase

Question 24

Gluconeogenesis

Answer 24

Helps to avoid hypoglycaemia by producing glucose from pyruvate/oxaloacetate

o Pyruvate converted to oxaloacetate by pyruvate carboxylase – occurs in mitochondria

o Reactions catalysed by kinases in glycolysis are irreversible, so phosphatases used to do reverse of reaction

o BYPASS REACTIONS - cytosolic

§ Oxaloacetate is converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase

§ Fructose-1,6-BisP converted to Fructose 6-P by fructose 1,6 bisphosphatase

§ Glucose 6-P converted to glucose by glucose 6 phosphatase

Question 25

Chylomicrons

Answer 25

Source : intestines
Role: dietary fat transport

Fats are absorbed by enterocytes in the brush border of the small intestine

o Triglycerides are incorporated into chylomicrons (CM) à transported in lymphatics to thoracic duct à left subclavian vein

o Lipoprotein lipase helps absorb fats à fatty acids then used for beta oxidation à located on capillary endothelial cells lining variety of tissues

o Chylomicrons acquire apoproteins from HDL following release into bloodstream which allow them to be recognised by liver

Question 26

Very low density lipoproteins (VLDL)

Answer 26

Source: liver
Role : endogenous fat transport

Transports fatty acids and cholesterol to muscles and adipose tissues
Glycerol reduced from the lipids returned to liver for use in gluconeogenesis

Becomes IDL after transfer of apoproteins to HDL

Question 27

Intermediate Density Lipoprotein (IDL)

Answer 27

Source : VLDL
Role: LDL precursor

HDL transfers cholesterol esters to IDL to form LDL

Question 28

Lipoprotein

Answer 28

Lipoproteins solve the problem of transporting hydrophobic molecules in an aqueous environment.

Phospholipid monolayer containing cholesterol and apoproteins.

This surrounds a core of cholesterol esters and triacylglycerols.

Question 29

Cholesterol esters

Answer 29

Synthesized in the plasma from cholesterol and the acyl chain of phosphatidylcholine (lecithin) via a reaction catalyzed by lecithin:cholesterol acyltransferase (LCAT).

The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol.

Question 30

High density Lipoproteins (HDL)

Answer 30

Good cholesterol

function to take cholesterol from peripheral tissues back to the liver for use or disposal (reverse cholesterol transport). They help to lower total serum cholesterol.

Contain 20% cholesterol esters
5% triglycerides

Question 31

Low density Lipoproteins

Answer 31

LDLs are often referred to as “bad cholesterol” as prolonged elevation of LDL levels leads to atherosclerosis (hardening of the arteries).

LDLs transport cholesterol synthesized in the liver to peripheral tissues with more than 40% of their weight made up of cholesterol esters.

Question 32

Ketone bodies

Answer 32

KBs are formed in liver & kidney mitochondria during prolonged fasting (low glucose),
- To be used by extra-hepatic tissues (including brain & RBCs which cannot use FAs) – note liver itself cannot use KBs
- Soluble in aq solution, do not need carriers
• KBs = acetoacetate & β-hydroxybutarate
-
-
-
synthesized from acetyl CoA, degraded to acetyl CoA Sweet-smelling breath (results e.g. from Atkins diet) KBs are acidic

Question 33

Cholesterol

Answer 33

Distinctive steroid nucleus (4 fused rings)
• Sources of hepatic cholesterol:
- Dietary cholesterol intake (transported via chylomicrons)
- De novo synthesis in liver
- Reverse transport of cholesterol from extrahepatic tissues (via HDL)
• Cholesterol cannot be metabolized
• Fate of hepatic cholesterol:
- Export to extra-hepatic tissues (via VLDL) for membrane, steroid, vit D synthesis
- Bile salt formation: 5% of bile salts excreted, 95% serving to emulsify dietary lipids and are reabsorbed via enterohepatic circulation
- Synthesis of vitamin D & steroid hormones

Question 34

Beta oxidation regulations

Answer 34

• Malonyl CoA inhibits CPT1 (reciprocal reg of breakdown & syn)
• Epinephrine & Glucagon ↑ cAMP, activating protein kinase A, phosphory-
lating and activating HSL while deactivating ACC, hence ↑ β-oxidation.
• Insulin dephosphorylates and has the opposite effect
• Long term regulation: transcriptional/translational control of enzyme amt

Question 35

Synthesis of Cholesterol

Answer 35

o Synthesis of cholesterol:

§ Synthesis of isopentenyl pyrophosphate, activated isoprene unit which serves as key building block (cytoplasm)

§ 2 x Acetyl CoA join together to form acetoacetyl CoA in condensation reaction by beta-ketothiolase

§ Acetoacetyl CoA reacts with acetyl CoA to form HMG-CoA by HMG-CoA synthase

§ HMG-CoA is reduced to produce mevalonate by NADPH with enzyme HMG-CoA reductase NOTE à enzymes is under intense negative feedback control by end product cholesterol, mevalonate + bile salts

§ Mevalonate phosphorylated at –OH groups three times by mevalonate kinase, phospho mevalonate kinase and kinase, followed by decarboxylation and removal of 1 phosphate to form 3-isopentenyl pyrophosphate

§ Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions)

§ 2 Isopentenyl pyrophosphate is used to produce dimethylallyl pyrophosphate via isomerization reaction via Geranyl transferase

§ Isopentenyl pyrophosphate added to dimethylallyl pyrophosphate to grow chain to 15C species farnesyl pyrophosphate via Geranyl transferase

§ 2 x farnesyl pyrophosphate condense to form 30C molecules squalene + 2 x pyrophosphate

§ Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)

§ Squalene reduced in presence of oxygen and NADPH to form squalene epoxide à different C=C bond distribution, priming for C ring fusion

§ Enzyme squalene epoxide lanosterol-cyclase catalyses formation of Lanosterol à series of 1,2 methyl group and hydride shifts along chain results in formation of 4 rings

§ Lanosterol is reduced and 3 methyl units removed to make cholesterol via 19 discrete steps

Question 36

Synthesis of bile salts

Answer 36

Key in emulsifying dietary fats due to hydrophobic + hydrophilic (from -OH groups) faces
Major breakdown product of cholesterols
Cholesterol converted but series’s of reactions into primary salt glycocholate + taurocholate

Question 37

Disorders of cholesterol metabolism - Familial Hypercholesterolemia

Answer 37

CAUSE
Deficiency of functional LDL receptors, increased protease degradation, or defects in apo B-100

RESULT
↑ Circulating cholesterol (not taken up) Hence ↓ inhibition of de novo synthesis

CONSEQ
May get heart attack young.

Question 38

Disorders of cholesterol metabolism - LDL & atherosclerosis

Answer 38

CAUSE
Triggered by ↑ LDL and ameliorated by antioxidants
RESULT
• Oxidizing agents conv LDL into oxoLDL, damaging vascular endothelium.
• oxoLDL taken up by macrophages (scavenger cells) via low-affinity,
nonspecific, nonregulated scavenger receptors
• Macrophages accumulate cholesterol and become foam cells
• Inflammatory response results in formation of atherosclerotic plaque

Question 39

Disorders of cholesterol metabolism - Cholelithiasis / Gallstones

Answer 39

CAUSE
Obstruction of biliary tract, intestinal malabsorption of bile acids, phospholipid metabolism disturbances.
RESULT
Cholesterol precipitates from bile when bile is supersaturated with cholesterol due to bile salt deficiency

Question 40

Eezetimbe

Answer 40

Lowers cholesterol by ↓ absorption of free cholesterol (and packaging into chylomicrons) fr GIT

Question 41

Statins (lower cholesterol)

Answer 41

inhibit de-novo synthesis (competitive inhibitors of HMG-CoA reductase)

• Hence ↑ LDL uptake: hepatocytes compensate for ↓ synthesis by ↑ LDL receptors to remove cholesterol from circulation
• Statins with short half-life taken at night to maximise effect since de novo synthesis occurs mainly at night

Question 42

Cholestyramine (Questran, Questran Light, Cholybar)

Answer 42

• Resin to bind bile acids in gut & reduce recycling
• Hence ↑ LDL uptake for bile acid synthesis

These bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine. They can lower LDL (“bad” cholesterol) by 15 -30% and raise HDL (“good” cholesterol) by 3 - 5%.

Question 43

Synthesis of steroids from cholesterol

Answer 43

The precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase. All five classes of steroid hormones come from pregnenolone: Progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens.

Question 44

Vitamin D

Answer 44

Vitamin D is a collective term for a group of steroids which are vital for the intestinal absorption of important ions needed for bone development, namely calcium, phosphate and magnesium. The bulk of the Western diet is low in vitamin D and our main source is from the activity of UV light upon 7-dehydrocholesterol in the epdermis of the skin.

 Calcitriol is the most active vitamin D metabolite and plays a key role in calcium metabolism. It functions as a steroid hormone, binding to vitamin D response elements (VDREs) in the promoter of target genes and inducing key genes involved in bone metabolism. A deficient of Vitamin D3 in childhood leads to rickets, a defect of bone development in children.

Question 45

Medium chain acyl-coenzyme A dehydrogenase deficiency (MCADD)

Answer 45

Autosomal recessive. Predominantly occurring in Caucasians.
Occurs 1 in 10,000 live births in the UK per year.
If undiagnosed, can be fatal

ω -oxidation more significant, shortened dicarboxylic acids (6-10C) excreted in urine
• Unoxidised MCFAs transferred back to carnitine and excreted in urine as acyl-carnitines.

If diagnosed, patients should never go without food for longer than 10–12 hours (a typical overnight fast). Adhere to a high carbohydrate diet.
Patients with an illness resulting in appetite loss or severe vomiting may need i.v. glucose to make sure that the body is not dependent on fatty acids for energy.

Question 46

After lipogenesis

Answer 46

Elongation of the acyl group to make fatty acids longer than 16 carbons occurs separately from palmitate synthesis in the mitochondria and endoplasmic reticulum (ER).

Desaturation of fatty acids requires the action of fatty acyl-CoA desaturases

The enzyme that creates oleic acid and palmitoleic acid from stearate and palmitate, respectively, is called a ∆-9 desaturase, as it generates a double bond nine carbons from the terminal carboxyl group.

Question 47

Anaerobic respiration

Answer 47

Under anaerobic conditions, the demands of the contracting muscle for ATP cannot be met by oxidative phosphorylation and similarly, the transport of glucose from the blood cannot keep up with the demands of glycolysis.

Glycogen within the muscle is therefore broken down to meet these demands. To replenish NAD+ levels and maintain glycolysis, pyruvate is taken up by the liver and converted into lactate by lactate dehydrogenase (MBC-Cell metabolism 1 ). Lactate can then be used by the liver to generate glucose by gluconeogenesis.

Question 48

Aerobic respiration

Answer 48

During moderate levels of exercise, where oxygen supply is adequate, the ATP demands of muscle can be met by oxidative phosphorylation using glucose and other substrates as fuels.



Glucose is transported from the blood into muscle cells where it can undergo metabolism by glycolysis and the TCA cycle to ultimately generate ATP by the re-oxidation of cofactors.



As muscle contracts, the demand for ATP increases e.g. requirements of muscle actomyosin ATPase and cation balance. Increased demand for glucose is met by an increase in the number of glucose transporters on the membranes of muscle cells.



Adrenalin plays a key role in meeting the demand for ATP by increasing the rate of glycolysis in muscle, increasing the rate of gluconeogensis by the liver (red dashed arrows) and increasing the release of fatty acids from adipocytes.

Question 49

Creatine Kinase

Answer 49

Creatine kinase (CK) is probably present in all cells but is present in particularly high concentrations in muscle cells and brain cells. Following the damage or death of such cells CK is released into the circulation.

Three dimeric isoenzymes of creatine kinase are known in humans. The two different subunits M and B provide the following isoenzymes: MM, MB and BB. The only human tissue where the MB form is found is the myocardium, where MB represents about 15% of total creatine kinase, the rest being MM.

Question 50

Cell Death in Myocardial Infarction

Answer 50

What is a myocardial infarct?

It is the death of heart muscle cells.

Why do the cells die?

Lack of oxygen.

Why is there a lack of oxygen?

Blockage of the cardiac arteries. This process is termed atherosclerosis and you might like to ponder on what kind of things might be risk factors for its early development.

Why do cells need oxygen, how do they use it and why do cells die without it?

What constitutes a cell i.e. a semi-permeable membrane separating the inside from the outside?

There is active exclusion of some things such as Na+ ions.
​This needs a protein pump in the membrane.
These are a type of enzyme called membrane ATPases.
They use energy in the form of adenosine triphosphate (ATP) to pump ions.
How is ATP generated? Via glycolysis, the Krebs Cycle and eventually oxidative phosphorylation.
The end point of the process requires atmospheric oxygen, hence if there is less oxygen supplied to a cell there is less ATP, pumps do not function, ion balance is lost and cells die.
Cell contents are released when they are dying, i.e. proteins that should be held inside against concentration gradients appear in the serum.

Therefore the levels of many proteins including creatine kinase (many others as well such as lactate dehydrogenase) in serum can be used as indirect indicators of cell death.

Question 51

Where is Creatine Kinase (CK) normally present?

Answer 51

CK is present in all cells at very low levels but is at high concentrations in metabolically very active tissues including the brain, heart and skeletal muscle. Creatine phosphate is an energy store.

CK activity in the serum can be detected by a coupled assay (Figure 1) leading to the generation of detectable products. Recall from the Introduction to Laboratory Techniques event that NADH (and NADPH) have absorption spectra distinct from NAD+ (and NADP+).

Creatine phosphate + ADP - (CK) -> creatine + ATP
D-glucose + ATP - (hexokinase)-> ADP + G6P
G6P + NADP+ - (G6P dehydrogenase)-> 6-PG +NADPH + (H+)

Question 52

Alcohol fermentation of pyruvate

Answer 52

Pyruvate -(pyruvate decarboxylase + H+) -> acetaldehyde + CO2
Acetaldehyde -(alcohol dehydrogenase +NADH + H+)-> ethanol + NAD+

Question 53

Lactate production form pyruvate

Answer 53

Pyruvate lactate

(NADH + H+ -> NAD+)

Question 54

Acetyl CoA production from pyruvate

Answer 54

Pyruvate + Hs-CoA - (pyruvate dehydrogenase complex ) -> Acetyl-CoA + CO2

Occurs on the outer membrane of the mitochondria

Question 55

Dinitrophenol

Answer 55

can induce weight loss by transporting protons across the mitochondrial membrane, thereby uncoupling oxidative phosphorylation from ATP production and markedly increasing the metabolic rate and body temperature.

Subsequently it soon found its way into numerous patented “anti-fat” medicines for the treatment of obesity. However, the margin between the slimming dose and that required to poison or kill is slight - so slight that several patients died and many suffered permanent injury before use of the drug was abandoned in 1937.

Question 56

Liver Cirrhosis (fatty liver)

Answer 56

• High NADH/NAD+ inhibits FA oxidation
• FAs re-esterified into TGs
- Rate of re-esterification enhanced because NADH favours production of glycerol-3- phosphate from dihydroxyacetone phosphate
- Fatty acyl CoA transferases inducible by ethanol consumption
• Chronic accumulation results in fatty liver development

Question 57

Toxic effect of alcohol-> hypoglycaemia and acidosis

Answer 57

• As there is no feedback regulation of ADH & ALDH (NADH is not an effective product inhibitor), NADH is formed faster than it can be oxidized by ETC, resulting in NADH accumulation
• Balance in lactate dehydrogenase rxn shifted towards forming lactate from pyruvate (after all whole purpose of lactate formation is to regenerate NAD+ so glycolysis can continue)
- Lactic acidosis
- Due to acidosis, ↓ uric acid excretion by kidney (problems in gout patients)
- ↓ pyruvate availability for pyruvate carboxylase, inhibiting gluconeogenesis. In a
fasting individual (no glycogen stores), this can cause hypoglycemia
• Enough NADH generated from oxidation of ethanol and fatty acids that there is no need to oxidise acetyl CoA in TCA cycle
- Shunt acetyl-CoA to produce ketone bodies - Ketoacidosis

Question 58

Hormonal control of blood glucose level

Answer 58

-Insulin is secreted when glucose levels rise: it stimulates uptake and use of glucose and storage as glycogen and fat.
-Glucagon is secreted when glucose levels fall: it stimulates production of glucose by gluconeogenesis and breakdown of glycogen and fat.
(both are secreted by islets of the pancreas)

• Adrenalin (or epinephrine): strong and fast metabolic effects to mobilise glucose for “flight or fight”.
• Glucocorticoids: steroid hormones which increase synthesis of metabolic enzymes concerned with glucose availability.

On having a meal, blood glucose levels initially rise which is controlled by increased secretion of insulin (and reduced glucagon) from islets.

This has several effects including:

1. Increased glucose uptake by liver – used for glycogen synthesis and glycolysis (acetyl-CoA produced is used for fatty acid synthesis).
2. Increased glucose uptake and glycogen synthesis in muscle.
3. Increased triglyceride synthesis in adipose tissue.
4. Increased usage of metabolic intermediates due to a general stimulatory effect on the body’s synthesis and growth.
   
   After a meal blood glucose levels start to fall and are controlled by:
5. Increased glucagon secretion (and reduced insulin) from islets.
6. Glucose production in liver resulting from glycogen breakdown and gluconeogenesis.
7. Utilisation of fatty acid breakdown as alternative substrate for ATP production (important for preserving glucose for brain).

[NB adrenalin has similar effects on liver, but also stimulates skeletal muscle towards glycogen breakdown and glycolysis, and adipose tissue towards fat lipolysis to provide other tissues with alternative substrate to glucose]

After prolonged fasting (i.e. longer than can be covered by glycogen reserves):

1. glucagon/insulin ratio increases further
2. adipose tissue begins to hydrolyse triglyceride to provide fatty acids for metabolism
3. TCA cycle intermediates are reduced in amount to provide substrate for gluconeogenesis
4. Protein breakdown provides amino acid substrates for gluconeogenesis
5. Ketone bodies are produced from fatty acids and amino acids in liver to substitute partially the brain’s requirement for glucose

Question 59

Diabetes mellitus

Answer 59

Diabetes mellitus is a disorder of insulin release and signalling, resulting in an impaired ability to regulate blood glucose concentrations.

There are two main types of diabetes mellitus:

Type I diabetes in which individuals fail to secrete enough insulin (β-cell dysfunction).
Type II diabetes in which individuals fail to respond appropriately to insulin levels (insulin resistance).


The overall effect is that metabolism is controlled as if the person is undergoing starvation, regardless of dietary glucose uptake.

Complications of diabetes include:

1. Hyperglycaemia with progressive tissue damage (e.g. retina, kidney, peripheral nerves)
2. Increase in plasma fatty acids and lipoprotein levels with possible cardiovascular complications
3. Increase in ketone bodies with the risk of acidosis
   hypoglycaemia with consequent coma if insulin dosage is imperfectly controlled

Glucagon is important in protection against hypoglycaemia.

A major site of action is the liver where glucagon stimulates gluconeogenesis and glycogenolysis.
Insulin deficiency and relative excess of glucagon leads to increased hepatic output of glucose and, thus, hyperglycaemia.