Fundamentals: Physiology - General principles of medical physiology Flashcards
Describe the average body composition of a young adult male (in terms of proportions of protein, fat, mineral and water - and the composition of that water)
18% protein
15% fat
7% mineral
60% water (20% ECF with 5% blood plasma and 15% interstitial fluid; 40% intracellular fluid)
I.e. about 1/3 of total body water is ECF and 2/3 is ICF
What % of body weight is the total blood volume?
8%
Describe the differences in fluid and electrolyte composition between extracellular and intracellular compartments (in terms of cation and anion balance)
Extracellular fluid:
- Cation balance largely Na (minimal K)
- Anion balance largely Cl
- Some protein in plasma, not much in interstitial fluid
Intracellular fluid:
- Cation balance largely K
Anion balance largely protein and miscellaneous phosphates
What is interstitial fluid?
Fluid outside of vascular and lymphatic systems which bathes the cells
What bridges the blood plasma and interstitial fluid?
Lymph fluid bridges the two domains
What is a mole?
The gram-molecular weight of a substance
Each mole consists of 6x10^23 molecules
What is a millimole? What is a micromole?
Millimole: 1/1000 of a mole
Micromole: 1/1,000,000 of a mole
How much does 1 mole of NaCl weigh in g?
NaCl = 23g Na + 35.5g Cl = 58.5g/mol
What is the molecular weight of a substance
Ratio of mass of one molecule of the substance to the mass of one-twelfth the mass of a carbon-12 atom
What is the dalton?
Equal to one-twelfth the mass of a carbon-12 atom
What is an equivalent?
One mole of an ionised substance divided by its VALENCE
What is one Eq of sodium? What is one Eq of calcium?
One Eq of sodium (Na+) = 23g
One Eq of calcium (Ca2+) = 40/2 = 20g
What is a gram equivalent?
A gram equivalent is the weight of a substance that is chemically equivalent to 8g oxygen (or 35.5g Cl, or…)
What is normality? Give an example using a 1N solution of HCl
Normality (N) of a solution is the number of gram equivalents in 1L (i.e. g/L)
A 1N solution of HCl contains both H+ (1g) and Cl- (35.5g) equivalents = 36.5g/L
What is pH?
The pH of a solution is the logarithm to the base 10 of the reciprocal of the hydrogen ion concentration
For each pH unit <7, the concentration of hydrogen is increased tenfold and >7, it is decreased tenfold
What is a buffer? Give an example
A buffer is a substance that has the ability to bind or release H+ in solution, thus keeping the pH of the solution relatively constant
Consists of a weak acid and its conjugate base
E.g. carbonic acid, moving the equilibrium point depending on additional H+ or OH-
What makes H2O such an excellent biological fluid? List 3 reasons
- Serves as a solute (has a high surface tension)
- Provides optimal heat transfer (has a high heat of vaporisation and heat capacity)
- Provides optimal conduction of current (has a high dielectric constant)
What are electrolytes?
Molecules that dissociate in water to their cation and anion equivalents
What is the pH of gastric fluid?
3
What is the pH of pancreatic secretions?
8
What is an acid?
A molecule that acts as a H+ donor in solution
What is a base?
A molecule that tends to remove H+ in solution
Describe the isohydric principle
All buffer pairs in a homogenous solution are in equilibrium with the same H+
All buffer systems which participate in defence of acid-base changes are in equilibrium with each other
How is the relationship for dissociation of acid in solution defined mathematically?
According to the laws of mass action, a relationship for dissociation can be defined mathematically as:
Ka = [H+][A-]/[HA]
What is the Henderson-Hasselbalch equation? When is the buffering capacity of a weak acid best?
pH = pKa + log[A-]/[HA]
Buffering capacity of a weak acid is best when the pKa of that acid is equal to the pH of the solution (i.e. [A-] = [HA], pH = pKa)
Outline the equation for the bicarbonate buffer system
H2CO3 (carbonic acid) <-> H+ + HCO3- <-> H2O + CO2
What is diffusion?
The process by which a gas or a substance in solution expands or moves from one region to another, because of the motion of its particles, to fill all of the available volume
Explain Fick’s law of diffusion
The magnitude of the diffusing tendency from one region to another separated by a boundary is directly proportional to the cross-sectional area across which diffusion is taking place, and the concentration gradient or chemical gradient
J = −DA x (∆c/∆x)
where J = net rate of diffusion, D = diffusion coefficient, A = area, and Δc/Δx = concentration gradient
What is osmosis?
Diffusion of solvent molecules into a region in which there is a higher concentration of solute to which the membrane is impermeable
What is osmotic pressure? What is it dependent on?
Pressure necessary to prevent solvent migration
Dependent on the number rather than the type of particles
What is an ideal solution?
A solution in which the enthalpy of solution is zero
What is the relation between osmotic pressure, temperature and volume in an ideal solution?
In an ideal solution, the osmotic pressure (P) is related to temperature and volume in the same way as the pressure of a gas
P = nRT/V
where n = number of particles, R = gas constant, T = absolute temperature, and V = volume
If T is held constant, then the osmotic pressure is proportionate to the number of particles in solution per unit volume
What is an osmole?
Unit used to express the number of osmotically active particles
1 Osm = gram-molecular weight of a substance divided by number of freely moving particles that each molecule liberates in solution
E.g. one mole of NaCl would dissociate into Na+ and Cl- ions, supplying 2 Osm
Why does why 1mmol of NaCl per L in body fluids contribute somewhat less than 2 mOsm of osmotically active particles per L?
Body fluids are not ideal solutions: although the dissociation of strong electrolytes is complete, the number of particles free to exert an osmotic effect is reduced owing to interactions between the ions
What is the difference between osmolarity and osmolality?
OSMOLARITY is the number of osmoles per litre of solution (e.g. plasma)
OSMOLALITY is the number of osmoles per kilogram of solvent
What is tonicity? Explain the difference between isotonic, hypertonic and hypotonic solutions
Term used to describe the osmolality of a solution relative to PLASMA
Same osmolality as plasma = ISOTONIC
Greater osmolality = HYPERTONIC
Lesser osmolality = HYPOTONIC
How can the tonicity of a solution change? Give an example
All solutions that are initially isotonic would stay that way were it not for the fact that some solutes diffuse into cells and others are metabolised
Normal saline thus remains isotonic as there is no net movement of the osmotically active particles into the cells and the particles are not metabolised
However, 5% glucose solution is isotonic initially, but glucose is metabolised, so the net effect is infusing a hypotonic solution
How many mOsm are in a litre of normal plasma? How many of these mOsm are contributed by Na and its associated anions (predominantly Cl and HCO3)? How much is contributed by glucose and urea?
290 mOsm
All but 20 mOsm are Na and associated anions
Glucose and urea contribute about 5 mOsm each
Why is the concentration of plasma proteins large when expressed in grams per L yet contributes little in the way of osmolality?
Because of their very high molecular weights (i.e. high in weight but less in number - less in osmotically active particles)
How is cell volume regulated?
Swelling activates channels permitting efflux of potassium and chloride, with water following and returning cell to normal volume
Without these channels cells would swell and burst when exposed to extracellular hypotonicity, and shrink when exposed to hypertonicity
What is non-ionic diffusion?
Some weak acids and bases are soluble in cell membranes in the undissociated form, whereas they cross membranes poorly in the ionic form
If substances diffuse then dissociate, there is appreciable net movement of the undissociated substance
Explain the Donnan effect
In the presence of a non-diffusible ion, the diffusible ions distribute themselves so that at equilibrium their concentration ratios are equal
The Gibbs-Donnan effect describes the unequal distribution of permeant charged ions on either side of a semipermeable membrane which occurs in the presence of impermeant charged ions.
At Gibbs-Donnan equilibrium,
On each side of the membrane, each solution will be electrically neutral
The product of diffusible ions on one side of the membrane will be equal to the product of diffusible ions on the other side of the membrane
The electrochemical gradients produced by unequal distribution of charged ions produces a transmembrane potential difference which can be calculated using the Nernst equation
The presence of impermeant ions on one side of the membrane creates an osmotic diffusion gradient attracting water into that compartment
What is the Nernst equation?
The electrochemical gradients produced by unequal distribution of charged ions (Donnan effect) produces a transmembrane potential difference which can be calculated using the Nernst equation
ECl = ({RxT}/{FxZCl}) x ln ([Clo]/[Cli])
where ECl = equilibrium potential for Cl, R = gas constant, T = absolute temperature, F = the Faraday number (number of coulombs per mole of charge), ZCl = valence of Cl (-1), [Clo] = Cl concentration outside the cell, and [Cli] = Cl concentration inside the cell
What are the three physiological implications of the Donnan effect?
- Because of intracellular proteins, there are more osmotically active particles in cells than in the interstitial fluid
- Cells maintain their normal volume and don’t swell and rupture because of the Na/K ATPase which pumps ions back out of the cell
- This, along with the selective permeability of the cell membrane, also explains why Na+ and K+ maintain relatively constant intracellular concentrations despite the net result of passive and electrical forces being a gradual gain of Na+ and loss of K+ within the cell - Because there is an asymmetrical distribution of permeant ions across the membrane, an electrical difference exists across the membrane whose magnitude can be calculated using the NERNST EQUATION
3. Since there are more proteins in plasma than in the interstitium, there is a Donnan effect on ion movement across the capillary wall
Describe the movement of potassium in and out of the cell
The concentration gradient for K+ facilitates its movement out of the cell via K + channels, but its electrical gradient is in the opposite (inward) direction
At equilibrium, what is the balance of cations and anions in and outside of the cell? How is this maintained?
At equilibrium, there is a slight excess of cations on the outside and anions on the inside
This condition is maintained by the Na/K ATPase
How does the Na/K ATPase contribution the establishment of the membrane potential?
Because the Na/K ATPase moves three Na+ out of the cell for every two K+ moved in, it also contributes to the membrane potential, and thus is termed an electrogenic pump
Where is energy used in cellular functions stored? How is it released?
Energy is stored in bonds between phosphoric acid residues and certain organic compounds
Because the energy of bond formation is particularly high in some cases, relatively large amounts of energy are released when the bond is hydrolysed
Give two examples of a high-energy phosphate
Adenosine triphosphate (ATP) -> hydrolysed to ADP
Creatine phosphate (found in muscle)
What is coenzyme A?
CoA is a widely distributed thioester (acyl derivative of mercaptan) coenzyme that reacts with acetic acid to form acetyl-CoA
Acetyl CoA combines readily with substances in reaction due to its high energy content
How many kcal/mol are released in high-energy vs low-energy phosphates?
High-energy: 10-12 kcal/mol
Low-energy (e.g. glucose 6-phosphate): 2-3 kcal/mol
Define oxidation
The combination of a substance with oxygen, or the loss of hydrogen, or loss of electrons
Define reduction
Reverse process to oxidation
Involves the gaining of hydrogen ion or electrons
What is the role of cofactors and coenzymes?
Cofactors (simple ions) or coenzymes are accessory substances that act as carriers for the products of the reaction
Unlike enzymes, coenzymes may catalyse a variety of reactions
A number of coenzymes acts as hydrogen acceptors
What is the flavoprotein-cytochrome system? Where does it occur? What are the steps involved
A chain of enzymes that transfers hydrogen to oxygen, forming water
Occurs in the MITOCHONDRIA
A common form of biological oxidation is removal of hydrogen from an R-OH group, forming R=O
NAD+ and NADP+ pick up hydrogen, forming NADH and NADPH
Hydrogen is then transferred to the FLAVOPROTEIN-CYTOCHROME SYSTEM, reoxidising the NAD+ and NADP+
Each enzyme in the chain is reduced and then reoxidised and then hydrogen is passed down the line
The final enzyme in the chain is CYTOCHROME C OXIDASE, which transfers hydrogens to O2, forming water
What is oxidative phosphorylation?
The principal process by which ATP is formed in the body
How does oxidative phosphorylation occur?
The process harnesses energy from a proton gradient across the mitochondrial membrane to produce the high-energy bond of ATP
What % of oxygen consumption in the basal state is mitochondrial? How much of this is coupled to ATP synthesis?
90% of oxygen consumption in the basal state is mitochondrial and 80% of this is coupled to ATP synthesis
What processes is ATP mostly used in?
Protein synthesis (27%)
Na/K ATPase to help set membrane potential (24%)
Gluconeogenesis (9%)
Ca ATPase to maintain low cytosolic Ca concentration (6%)
Myosin ATPase to provide energy for muscle contraction (5%)
Ureagenesis (3%)
What is normal osmolality and how is it calculated?
Normal osmolality is 275-290mOsm
Calculated osmolarity = (2 x [Na+]) + [glucose] + [urea])
What is the difference between osmolarity and osmolality?
Osmolality is the concentration per weight solvent (mmol/kg)
Osmolarity is the concentration solute per volume solvent (mmol/L)
What is the osmolar gap? What is the normal range and what is its clinical significance?
Osmolar gap = Osmolality (measured) –Osmolarity (calculated) - expressed in mmol/kg (although this doesn’t make mathematical sense)
Normal < 10
High osmolar gap indicates the presence of an abnormal solute in significant amounts (e.g. ethanol, mannitol, methanol, ethylene glycol, sorbitol, polyethylene glycol or propylene glycol - IV BZD, glycine - TURP syndrome, maltose - IVIg)
Define nucleoside
Sugar linked to a nitrogen-containing base
Define nucleotide and give 8 examples
Formed by the addition of an inorganic phosphate to a nucleoside
E.g. adenine, guanine, thymine, uracil, cytosine, ATP, NAD+, NADP+
Give two examples of physiologically important nitrogen-containing bases
Purine
Pyrimidine
Where are purine and pyrimidines synthesised?
Primarily in the liver
Define nucleic acid and give two examples
Many nucleotides forming double-helical structures of two polynucleotide chains
E.g. DNA, RNA (single-helical, single polynucleotide chain)
How do bases bond in DNA vs RNA?
Hydrogen bonds
DNA: A to T, C to G
RNA: A to U, C to G
Define gene
Sequence of DNA nucleotides containing the information for the production of an ordered amino acid sequence for a single polypeptide chain
What is an intron?
Gene segments that are not translated into amino acids
What is an exon?
Gene segments that are translated into amino acids
What is a promoter?
Gene sequence site at which RNA polymerase and its cofactors bind (often includes a TATA box)
Give two examples of gene regulatory elements
Enhancer and silencer sequences
What is an allele?
Version of a gene (two in a diploid cell)
What is a SNP?
Single nucleotide polymorphism
Change in single nucleotide within or outside coding regions of a gene which can have great consequences for gene function
How do gene mutations occur?
Occur when base sequence of DNA is altered from its original sequence (may be insertions, deletions, or duplications)
What is a point mutation?
Single base substitutions
What is a genome?
Collection of genes within the full expression of DNA from an organism
Define transcription
Production of RNA from DNA, catalysed by RNA polymerase
Outline the basic steps in transcription
Typical pre-mRNA transcription starts at cap site (7-methylguanosine triphosphate cap is necessary for ribosomal binding) and ends with a poly(A) tail of about 100 bases (aids mRNA stability)
What is posttranscriptional modification?
Post-transcriptional modification of pre-mRNA is a regulated process where differential splicing can occur to form multiple mRNA from a single pre-mRNA (e.g. via spliceosomes or self-splicing)
Define translation
Production of proteins from mRNA
Outline the 4 different types of RNA and their roles
Messenger RNA (mRNA): carry coding sequences for protein synthesis
Ribosomal RNA (rRNA): form the core of the cell’s ribosomes
Transfer RNA (tRNA): carry amino acids to the ribosomes during protein synthesis
MicroRNA: shown to negatively regulate gene expression at posttranscriptional level
Define nucleoprotein
Nucleic acid plus one or more simple basic proteins
How is uric acid formed?
Formed by purine breakdown (via reactions catalysed by xanthine oxidase) and by direct synthesis
Explain the difference between primary and secondary gout
In primary gout, there may be increased uric acid production because of enzyme abnormalities, or a selective deficit in renal tubular transport of uric acid
In secondary gout, uric acid levels in body fluids are elevated due to decreased excretion (e.g. with thiazide diuretics, in renal disease) or increased production (e.g. leukaemia and pneumonia due to increased breakdown of uric acid-rich white blood cells)
What is the mechanism action of colchicine?
Colchicine inhibits phagocytosis of uric acid crystals by leucocytes
What is the mechanism of action of probenicid?
Probenicid inhibits uric acid reabsorption in the renal tubules
What is the mechanism of allopurinol?
Allopurinol directly inhibits xanthine oxidase in the purine degradation pathway
Define mitosis and outline the steps
Somatic cell division
Prophase → metaphase → anaphase → telophase → cytokinesis
Define meiosis
Reductive cell division
Occurs in germ cells to produce gametes - mature germ cells with half the amount of chromosomal material found in somatic cells
Explain the stages of the cell cycle
Mitosis → G1 (Gap 1; centrioles duplicate - may exit cycle to G0, cell arrest, at this point) → S (DNA replication) → G2 (Gap 2; final growth and activity before mitosis)
Define aneuploidy
Condition in which a cell contains other than the haploid number of chromosomes (common in cancerous cells)
List the 8 nutritionally essential amino acids
Valine (Val)
Leucine (Leu)
Isoleucine (Ile)
Threonine (Thr)
Methionine (Met)
Phenylalanine (Phe)
Tryptophan (Trp)
Lysine (Lys)
List the 10 non-essential amino acids
Histidine
Arginine
What is a conditionally essential amino acid? List the 2 conditionally essential amino acids
Alanine (Ala)
Serine (Ser)
Cysteine (Cys)
Selenocysteine
Tyrosine (Tyr)
Asparagine (Asn)
Aspartic acid (Asp)
Glutamine (Gln)
Glutamic acid (Glu)
γ-carboxyglutamic acid (Gla)
Distinguish between a peptide, polypeptide, and protein
Peptide: molecules consisting of 2-100 amino acids
Polypeptide: molecules containing 11-99 amino acids
Protein: molecules containing 100 or more amino acids
What is a glycoprotein?
Glycoprotein: protein containing carbohydrates
What is a lipoprotein?
Lipoprotein: protein containing lipids
Distinguish between primary, secondary, tertiary, and quaternary structure of proteins
Primary structure: order of amino acids in the peptide chains
Secondary structure: spatial arrangement of peptide chains in a protein formed by twisting and folding (e.g. α-helix, β-sheet)
Tertiary structure: arrangement of twisted chains into layers, crystals, or fibres
Quaternary structure: arrangement of protein subunits into functional structure (e.g. in haemoglobin)
Outline the steps in translation
- Amino acids are activated by combination with an enzyme and AMP (adenylate), and each activated amino acid combines with a specific tRNA molecule
- The tRNA-amino acid-adenylate complex then attaches to the mRNA template in the ribosomes
- During protein synthesis, mRNA is attached to the 40S ribosomal subunit and the polypeptide chain attaches to the 60S ribosomal unit (tRNA attaches to both)
How is specificity of tRNA molecules achieved?
tRNA has a three-base triplet (codon) that is complementary to a set of three bases on the mRNA chain
What is a polyribosome?
It is common to have more than one ribosome on a given mRNA chain at a time, and the mRNA chain plus its collection of ribosomes is visible under the electron microscope as an aggregation of ribosomes called a polyribosome
What is the typical start and stop codon for an mRNA chain?
Typically starts with AUG, which codes for methionine
Stops at one of three stop, or nonsense, codons (UAG, UAA, UGA)
What is posttranslational modification? How is it achieved?
After formation of the polypeptide chain, further posttranslational modifications occur to produce the final protein
Involve reactions including hydroxylation, carboxylation, glycosylation, or phosphorylation of amino acid residues
What is the role of signal peptide and how is this achieved?
Signal peptide (leader sequence) guides proteins that are destined to be secreted or stored in organelles, and most transmembrane proteins, into the endoplasmic reticulum
Signal peptide binds to signal recognition particle (SRP), which stops translation until it binds to a translocon, a pore in the ER
How are proteins marked for degradation?
Conjugation of abnormal or aged normal proteins to the polypeptide ubiquitin marks them for degradation
Does ubiquitination always result in protein degradation?
No, can also play important role in protein-protein interactions and various cellular signaling pathways
Where does degradation of cytoplasmic proteins occur vs membrane proteins?
Ubiquitination of cytoplasmic proteins, including integral proteins of the ER, can mark the proteins for degradation in multisubunit proteolytic particles, or proteasomes
Ubiquitination of membrane proteins, e.g. growth hormone receptors, marks them for degradation, which can occur either in proteasomes or lysosomes
Where does oxidative deamination of amino acids occur?
In the liver
Outline the steps involved in oxidative deamination of amino acids
Imino acid is formed by dehydrogenation
This is then hydrolysed to the corresponding keto acid, with production of ammonium (NH4+)
Most of the NH4+ is converted to urea which is excreted in the urine
Why is ammonia increased in severe liver disease?
Most urea is formed in the liver and so in severe liver disease the blood urea nitrogen falls and ammonia (NH3) rises
What amino acids are ketogenic?
Leucine, isoleucine, pheylalanine and tyrosine are ketogenic (converted to ketone body acetoacetate)
What amino acids are gluconeogenic?
Alanine and many other amino acids are gluconeogenic (give rise to compounds readily converted to glucose)
Outline 6 important molecules formed from specific amino acids
Thyroid hormones, catecholamines, histamine, serotonin, melatonin, and intermediates in the urea cycle are formed from specific amino acids
Define carbohydrate
Organic molecules made of equal amounts carbon and H2O
Distinguish between monosaccharides, disaccharides, and polysaccharides (giving examples of each)
Monosaccharides: simple sugars, includes pentoses (five carbons, e.g. ribose) and hexoses (six carbons, e.g. glucose) which perform structural and functional roles
Disaccharides: made up of two monosaccharides (e.g. sucrose)
Polysaccharides: made up of more than two monosaccharides (e.g. glycogen)
What are the three most important/common carbohydrates? Describe their structure
Most dietary carbohydrates are hexose polymers, including glucose, galactose, and fructose
What is the product of carbohydrate digestion?
Glucose
What is normal fasting blood glucose?
3.9-6.1 mmol/L
Is plasma glucose higher in arterial or venous blood?
Arterial
Give a basic description of the steps involved in glucose metabolism
- Glucose is phosphorylated by hexokinase to form glucose-6-phosphate
- Glucose-6-phosphate is either polymerised into glycogen, the storage form of glucose (via a process called glycogenesis), or is catabolised to pyruvate or lactate via glycolysis
- Pyruvate is converted to acetyl-CoA
How can non-glucose molecules be converted to glucose? What is this process called?
Interconversions between carbohydrate, fat, and protein include conversion of glycerol (from fats) to dihydroxyacetone phosphate, and conversion of a number of amino acids with carbon skeletons resembling intermediates in the glucose catabolism pathway by deamination
Lactate can also be converted to glucose
This process is called gluconeogenesis
Why is there very little conversion of fat to glucose in the body?
Very little net conversion of fats to glucose in the body because apart from the quantitatively unimportant production from glycerol, there is no pathway for conversion
Glucose can be converted to fats through acetyl-CoA, but because conversion of pyruvate to acetyl-CoA is irreversible, fats are not converted to glucose via this pathway
What is lactose?
A disaccharide composed of glucose and galactose
How is galactose metabolised? What is the clinical significance of this?
Galactose is phosphorylated and reacts with UDPG to form uridine disphosphogalactose, which can be converted back into UDPG
Reversibility of UDPG formation provides the galactose necessary for formation of glycolipids and mucoproteins when dietary intake is inadequate
In galactosaemia, there is a congenital deficiency of galactose-1-phosphate uridyl transferase, meaning that ingested galactose accumulates in the circulation to cause serious disturbances in growth and development
Can be treated with galactose-free diet without leading to galactose deficiency, because the enzyme necessary for formation or uridine diphosphogalactose from UDPG is present (as outlined above)
What is the role of UDPG?
UDPG functions in glycogen synthesis
What are the two possible sources of fructose in the body?
Part is ingested, part is produced by hydrolysis of sucrose
What is the role of fructose 2,6-disphophate?
Important regulator of hepatic gluconeogenesis
Decreased levels of fructose 2,6-diphosphate increases gluconeogenesis
Contrast the pathways and energy yields of anaerobic vs aerobic metabolism
Anaerobic energy production occurs via the Embden-Meyerhof pathway only and produces only 2 mol ATP
Supply of NAD+ is needed, which in anaerobic conditions is formed via a reaction between pyruvate and NADH which also produces lactate
Aerobic energy production occurs via the Embden-Meyerhof pathway and citric acid cycle, to produce 38 mol ATP
Explain the concept of directional-flow valves in metabolism
Some reactions proceed in one direction under the influence of one enzyme or transport mechanism, and in the opposite direction under the influence of another (i.e. are not freely reversible)
Outline three factors that influence the plasma glucose level
Dietary intake (supply)
Rate of entry into cells of muscle, adipose tissue, and other organs (i.e. demand)
Glucostatic activity of the liver (supply and demand)
What % of ingested glucose is promptly converted into glycogen in the liver? What % is converted to fat? What happens to the remainder?
5% of ingested glucose is promptly converted into glycogen in the liver, and 30-40% into fat - remainder is metabolised in muscle and other tissues
What processes occur to maintain blood glucose levels during periods of fasting (and prolonged fasting)?
During fasting, glycogen is broken down to add more glucose to the bloodstream
During prolonged fasting when glycogen stores are depleted, there is increased gluconeogenesis from amino acids and glycerol in the liver
How many carbon atoms are in naturally occurring fatty acids?
An even number
Distinguish between saturated and unsaturated fatty acids
Saturated: no double bonds
Unsaturated: dehydrogenated, with various numbers of double bonds
Give three examples of typical fatty acids
Palmitic acid
Stearic acid
Oleic acid
Define triglyceride
Esters of glycerol and three fatty acids
Explain the composition and role of phospholipids
Made up of two fatty acids, a phosphate group, and a glycerol molecule
Constituents of cell membranes and provide structural components of the cell membrane, as well as an important source of intracellular and intercellular signaling molecules
Explain the composition and role of cerebrosides
Compounds containing galactose, fatty acid, and sphingosine
A complex lipid present in the sheath of nerve fibres
What is a sterol? Give three examples
Cholesterol and its derivatives
Includes steroid hormones, bile acids, and fat-soluble vitamins (A, D, E, K)
What is the name for the most common process by which fatty acids are broken down to acetyl-CoA? Where does this process mainly occur?
β-oxidation
Mainly occurs in the mitochondria
What is the difference in the metabolism process for long-chain fatty acids when compared with medium- and short-chain fatty acids?
Medium- and short-chain fatty acids enter mitochondria without difficulty, but long-chain fatty acids must be bound to carnitine to cross the inner mitochondrial membrane
How is carnitine synthesised?
Carnitine is synthesised from lysine and methionine
What does carnitine deficiency cause?
Carnitine deficiency results in deficient β-oxidation of fatty acids
Causes cardiomyopathy, as well as hypoketonaemic hypoglycaemia with coma (often triggered by fasting; glucose stores are used up because of the lack of fatty acid oxidation to provide energy, and ketone bodies are not formed in normal amounts because of the lack of adequate CoA in the liver)
How is carnitine deficiency treated?
Treated with L-carnitine supplementation
Paediatric patients may also benefit from a low-fat, high-carbohydrate diet and drinking more fluids
How are ketone bodies formed in the liver?
In many tissues, acetyl-CoA units condense to form acetoacetyl-CoA
In the liver, which contains a deacylase (unlike other tissues), free acetoacetate is formed instead
Acetoacetate is then converted to β-hydroxybutyrate and acetone
What are the three ketone bodies?
Acetoacetate
β-hydroxybutyrate
Acetone
In what kinds of circumstances can ketone bodies build up and produce a metabolic acidosis?
Ketone bodies are usually rapidly metabolised as they are formed, and a small amount is excreted in the urine
If entry of acetyl-CoA into the citric acid cycle is depressed because of a decreased supply of the products of glucose metabolism (e.g. in starvation, diabetes mellitus, or a high-fat low-carbohydrate diet), or if entry does not increase when acetyl-CoA is increased, it accumulates and forms more acetoacetate in the liver
This can then produce a metabolic acidosis
How does the energy yield from fat metabolism compare with that from carbohydrate metabolism?
In general energy yield from fatty catabolism is larger
What is the difference between structural lipids and neutral fat in terms of the response to starvation?
Neutral fat is stored in adipose cells of fat depots and mobilised during starvation (whereas structural lipid is preserved)
What is brown fat? Where is it located and how does its distribution change in adulthood?
Brown fat makes up a small percentage of total body fat and is more abundant in infants than adults
Plays role in heat production
Located between scapulas, at the nape of the neck, along the great vessels in the thorax and abdomen, and other scattered locations throughout the body
What are structural lipids?
Inherent part of membranes, can serve as progenitors for cellular signaling molecules
How is glucose stored as neutral fat?
In the adipose cells of fat depots, glucose is metabolised to fatty acids and neutral fats are synthesised; these can then be catabolised to release free fatty acids (FFAs) when needed
List the 6 main lipoproteins in the body in order from largest to smallest in size, and give their origin
Chylomicrons: intestine
Chylomicron remnants: capillaries
Very low-density lipoproteins (VLDL): liver, intestine
Intermediate-density lipoproteins (IDL): VLDL
Low-density lipoproteins (LDL): IDL
High-density lipoproteins (HDL): liver, intestine
How can FFAs be transported in the plasma?
Bound to albumin
What is the role and structure of a lipoprotein complex?
Cholesterol, triglycerides, and phospholipids form lipoprotein complexes to increase solubility and facilitate transport
Consists of a hydrophobic core of triglycerides and cholesteryl esters surrounded by phospholipids and protein
What are three important roles of cholesterol?
Essential constituent in cell membranes
Used by gland cells to make steroid hormones
Precursor of bile acids
How is FFA supply regulated? What are the impacts of fasting, feeding, stress and insulin on this process?
Supply of FFA is regulated by two lipases: lipoprotein lipase, and intracellular hormone-sensitive lipase of adipose tissue
Hormone-sensitive lipase activity is increased by fasting and stress, and decreased by feeding and insulin
Conversely, lipoprotein lipase activity is increased by feeding, and decreased by fasting and stress
What are the possible sources of cholesterol in the body?
Cholesterol is absorbed from the intestine and incorporated into chylomicrons, before being deposited in the liver
The liver and other tissues can also synthesise cholesterol
How does cholesterol help regulate its own production?
Cholesterol feeds back to inhibit its own synthesis by inhibiting HMG-CoA reductase
What is the mechanism of action of statins?
HMG-CoA reductase inhibitor
What are eicosanoids? How are they formed?
Precursors of prostaglandins, lipoxins, leukotrienes, and related compounds
Originate from the essential fatty acids
What are leukotrienes?
Local hormones which act as mediators of allergic responses and inflammation
What provokes the release of leukotrienes in allergy? What are some of the effects of leukotriene release?
Release is provoked when specific allergens combined with IgE antibodies on the surface of mast cells
Produce bronchoconstriction and arteriolar constriction, increase vascular permeability, and attract neutrophils and eosinophils to inflammatory sites
List some of the physiological effects of prostaglandins
Roles in:
- Female reproductive cycle
- Parturition
- Cardiovascular system
- Inflammatory responses
- Pain causation
