Gastrointestinal Physiology and Metabolism Flashcards
describe the 4 different types of secretory glands associated with the gastrointestinal tract
- Single cell mucous glands – e.g. goblet cells. Produce mucous in response to epithelial irritation
- Pit glands – e.g. crypts of Lieberkuhn. contain both goblet cells and enterocytes, which are specialised secretory cells producing digestive enzymes such as sucrose, maltase and enteropeptidase.
- Tubular glands – e.g. oxyntic glands. These branched glands are found in the stomach and are composed of several different cells which produce multiple secretions in response to food
- Complex glands – e.g. salivary glands. These lie outside the walls of the gastrointestinal tract and are composed of both acinar and ductal epithelial cells. The acini are lined with 3 different types of glandular cells whose primary secretions are modified by the ductal epithelium en route to the gastrointestinal tract.
describe the effect of increased parasympathetic activity on salivary gland function
increased acinar synthesis/secretion
increased ductal epithelial transport
increased blood flow via VIP, ACh
increased contraction of acinar myoepithelial cells
rapid flow of enzyme-rich saliva
Outline bilirubin metabolism and excretion
it is a breakdown product of haemoglobin
transported in the blood bound to albumin
conjugated to glucuronic acid in liver to form bilirubin glucuronide which is excreted into bile canaliculi and ducts
Intestinal bacteria then convert conjugated bilirubin to urobilinogen
circulating urobilinogen = urobilin
intestinal urobilinogen = stercobilin
Outline how bile secretion is controlled
The mixture is secreted into the bile canaliculi to the common hepatic duct and then stored and concentrated in the gall bladder.
The presence of fatty acids in the duodenum after a meal stimulates CCK release from I cells which induces gall bladder contraction, relaxation of the sphincter of Oddi, and emptying of bile into the intestine via the common bile duct.
Describe the functions of bile salts
bile salts act as a detergent to decrease surface tension and promote emulsification of fat particles, creating a large surface area for the action of lipases.
Bile salts then combine with lipid digestion products (monoglycerides, free fatty acids) to form micelles
Micelle formation is necessary for efficient fat absorption since it maintains a large surface area for lipid diffusion across the mucosal epithelium.
what is jaundice and describe the three forms of jaundice
Jaundice occurs due to elevated levels of plasma bilirubin leading to yellow discolouration of the eyes, skin and mucous membranes
- Pre-hepatic jaundice:
- due to haemolysis
- excess bilirubin production
- increased levels of circulating bilirubin
- e.g. sickle cell anaemia, haemolytic disease of the newborn - Hepatic:
- inability of liver to conjugate/excrete bilirubin
- e.g. hepatitis, alcoholic liver disease - Post-hepatic:
- obstruction of bile duct
- e.g. gallstones, pancreatic carcinoma
Explain the role of epithelial digestive enzymes
The cells of the intestinal mucosa also play an important digestive function, particularly in relation to carbohydrates. Oligosaccharides and polypeptides are present in the small intestine as a result of carbohydrate digestion by pancreatic α-amylase and protein digestion by pepsin/proteases. However, the intestine is unable to absorb these and further digestion is necessary to produce monosaccharides and amino acids. This is mediated by oligosaccharidases and peptidases which are bound to enterocytes of the crypts of Lieberkuhn covering the epithelium of the intestinal brush border with their active sites exposed to the luminal contents.
oligosaccharidases digest monosaccharides;
peptidases digest amino acids
Describe how the small intestine is specialised for absorption
The luminal surface of the small intestine is suitably adapted for absorption by possessing both specific transport mechanisms and a large surface area
Increase absorptive SA:
- mucosa - into macroscopic folds which project up into lumen.
- Microscopic mucosal projections, known as villi, which contain their own blood supply and lacteal.
- Folding of the epithelial membrane produces numerous microvilli, giving rise to the term epithelial brush border
Outline the absorption mechanisms for carbohydrates
Carbohydrates absorbed as monosaccharides (glucose, galactose, fructose)
Absorption of glucose and galactose occurs via secondary active transport, energy being provided by the Na+/K+ ATPase on the basolateral membrane. The process is Na+-dependent and relies on a Na+ co-transport carrier molecule in the luminal epithelial membrane to move monosaccharides against the concentration gradient.
In contrast, fructose absorption across the apical membrane occurs by facilitated diffusion. This requires a diffusion gradient from the intestinal lumen into the epithelium, the carrier molecule (GLUT5) simply acting to decrease the diffusion barrier created by the fatty cell membrane.
high intracellular concentrations of monosaccharides generated during absorption generate the concentration gradients required for these nutrients to diffuse across the basolateral membrane into the mucosal capillaries. For all monosaccharides, this process occurs via facilitated diffusion linked to a carrier protein (GLUT2) to increase the rate of transport through the lipid membrane.
see lecture 4 for diagram
Outline the absorption mechanisms for proteins
Proteins absorbed as short peptides and amino acids via secondary active transport
using an H+ co-transport system
H+ gradient across the apical membrane is created by a luminal Na+/H+ exchanger, the energy for the process being provided by the Na+/K+ ATPase on the basolateral membrane
Several specific carrier molecules are required to link H+ movement to transport of different peptides and amino acids
Absorbed short peptides are then degraded by intracellular peptidases before transport of amino acids across the basolateral membrane into the mucosal capillaries occurs via facilitated diffusion.
see lecture 4 for diagram
Outline the absorption mechanisms for lipids
see lecture 4 for diagram
Outline the absorption mechanisms for sodium and water
see lecture 4 for diagram
Outline the absorption mechanisms for lipids
see lecture 4 for diagram
Pancreatic lipase hydrolises triglycerides to form fatty acids and monoglycerides
these are Transported to epithelial border in micelles
Monoglycerides, FFAs enter the epithelial membrane by diffusion at the apical membrane
Monoglycerides and free fatty acids are then reconstituted into triglycerides by intracellular enzymes before being taken up by the endoplasmic reticulum and packaged within a lipoprotein coat to form chylomicrons
leave the mucosal epithelium through the basolateral lateral membrane via exocytosis, but as they are too large to enter the mucosal capillaries they pass into the intravillous lymphatics (lacteals).
then returned to the blood via the lymphatic system
Micelles recycled to ferry more lipid
Outline the absorption mechanisms for sodium and water
see lecture 4 for diagram
Water:
- mostly osmosis
- Dilute chyme which decreases intestinal osmolarity and therefore favours absorption of water
Sodium:
- primary active transport of Na+ out of the epithelial cells (via a Na+/K+ ATPase on the basolateral membrane) into the paracellular space between adjacent cells is followed by electrostatic diffusion of Cl-
- this creates an osmotic gradient in the paracellular space and therefore water moves in via osmosis
- less Na+ in the cell so Na+ from intestine moves in via facilitated dissuasion
- Movement of Na+ and H2O into the paracellular space elevates hydrostatic pressure and fluid is forced out into the interstitium
- this helps absorption into mucosal cellsmutual dependence of Na+ and nutrient absorption
Outline the absorption mechanisms for vitamins
see lecture 4 for diagram
FAT-SOLUBLE VITAMINS (A, D, E & K):
- absorbed with fats in which they are dissolved
WATER-SOLUBLE VITAMINS (e.g. C, B2, Folic acid):
- generally diffuse across intestinal mucosa if taken in sufficiently high doses
VITAMIN B12:
- needs intrinsic factor which comes from parietal cells
- Intrinsic factor binds to vitamin B12 in the intestine
- forms a dimer
- protective against digestion and allows binding to the epithelial cell membrane receptor
- Vitamin B12 dissociates from intrinsic factor within the cell and is carried in the blood bound to transcobalamin II
Outline the absorption mechanisms for calcium
see lecture 4 for diagram
- requires vitamin D - can get from diet and skin
- regulated by parathyroid hormone
- Parathyroid hormone promotes renal activation of vitamin D
- increases levels of Ca2+ binding protein in the mucosal epithelium
- increases activity of the Ca2+ ATPase in the basolateral membrane
- increasing intestinal Ca2+ absorption
- The activity of parathyroid hormone is inhibited by elevated plasma Ca 2+ levels thereby providing negative feedback regulation of intestinal Ca2+ absorption.
Outline the absorption mechanisms for iron
see lecture 4 for diagram
- ferrous (Fe2+), rather than ferric (Fe3+), ions are absorbed
- relies on binding to a transport protein, known as transferrin
- Fe2+-transferrin complex then binds to an epithelial membrane receptor
- passes into the cell by endocytosis
- inside the mucosal epithelium, the Fe2+ is released from transferrin as is absorbed into the circulation, where it becomes bound to plasma transferrin.
- In iron deficiency (e.g. following blood loss) the ability to absorb iron is increased, with an increased density of membrane receptors for the iron-transferrin complex.
what can deficiency in vitamin B12 cause
Deficiency of vitamin B12 most commonly results from pernicious anaemia, an autoimmune disease in which antibodies are produced against parietal cells leading to intrinsic factor deficiency and malabsorption of vitamin B12.
Define metabolism and metabolic rate
Metabolism = Sum of
CATABOLIC + ANABOLIC pathways
Sum of all chemical processes involved in:
- Producing energy from exogenous (eg food) and endogenous (eg glycogen) sources
- Synthesising and degrading structural and functional tissue components
- Disposing of resultant waste products
Conversion of chemical energy to other forms of energy
Define energy balance and describe situations that affect it
In the steady state INPUT OF FOOD = OUTPUT OF WORK/HEAT
Input of food is balanced against the output of work and heat generated in support of key metabolic processes, such as:
(1) mechanical work of muscle contraction, cell movement
(2) synthetic reactions required for fuel storage, tissue building, generation of essential functional molecules;
(3) membrane transport - minerals, ions and amino acids;
(4) generation and conduction of electrical, chemical and mechanical signals;
(5) heat production for temperature regulation and as a result of inefficient chemical reactions; and
(6) detoxification and degradation
POSITIVE ENERGY BALANCE needed in childhood, pregnancy, post-illness/trauma
Describe mechanisms that influence energy intake
regulated by hypothalamus
- lateral nuclei of the hypothalamus - house the main feeding centre, stimulation of which increases the desire for food
- ventromedial nuclei serve as the satiety (feeling full) centre - if this stimulated - inhibits the feeding centre
two distinct types of neurons in the arcuate nuclei:
- proopiomelanocortin (POMC) neurons:
- which secrete (alpha)-melanocyte-stimulating hormone ((alpha)-MSH) and cocaine- and amphetamine-related transcript (CART)
- reduce food intake - orexigenic neurons:
- secrete neuropeptide Y (NPY) and agouti-related protein (AGRP)
- increase food intake
Short term regulation:
- nutrient related signals:
- decreased glucose/FFAs = increased food intake
- increased cholecystokinin (CCK) / glucagon-like peptide-1 (GLP-1) = decreased food intake
- GI distension = vagal inhibitory signals = decreased desire for food
Long term regulation:
- sensing of energy stores:
- increased leptin/insulin = decreased food intake
- Overfeeding = positive energy balance = less reward for food, increased satiety (fullness), decreased food intake
- Energy deprivation = negative energy balance = more reward for food, decreased satiety, increased food intake
what is the equation for BMI, and what are healthy, overweight and obese values
weight in kg divided by height in m2
- BMI between 20 and 25 = healthy
- clinical terms a BMI of 25-30 = overweight
- > 30 = obese
what is the equation for BMI, and what are healthy, overweight and obese values
weight in kg divided by height in m2
- BMI between 20 and 25 = healthy
- clinical terms a BMI of 25-30 = overweight
- > 30 = obese
- not a direct measure adiposity and does take in to account increased muscle mass
what % body fat is considered obese in men and women
% body fat – obesity defined as >25% in men and >35% in women
Explain the central role of glucose in carbohydrate metabolism
- Carbs absorbed as monosaccharides - glucose, galactose, fructose
- Monosaccharides undergo enzymatic hepatic interconversion to glucose
- large amounts of glucose phosphatase in liver cells - this converts glucose-6-phosphate to glucose
- glucose is final common pathway for transport of carbs to tissue cells
- glucose high molecular weight so needs facilitated diffusion
- glucose transporters
- from high to low conc
Show how insulin secretion is regulated
insulin secretion turned off by reduced circulating glucose levels
amino acids:
- mainly arginine and lysine
- stimulate insulin secretion - promotes efficient protein metabolism
gastrointestinal hormones:
- eg gastrin CCK, GIP and GLP-1
- promote secretion
- as an anticipatory response
Autonomic nervous system:
- secretion reduced by sympathetic and increased by parasympathetic
describe the metabolic actions of insulin
in adipose tissue:
- increase glucose uptake
- increase lipogenesis
- decrease lipolysis
describe the effects of insulin on glucose metabolism
Insulin increases facilitated diffusion of glucose
Insulin promotes hepatic glucose metabolism:
- increase in insulin:
> increase in glucokinase - increase glucose uptake
> increase glycogen synthetase - increase glycogen storage
- decrease in insulin:
> increased activity of liver phosphorylase - increased glycogen breakdown
> increase activity of phosphatase - increased glucose release
describe the effects of insulin on glucose metabolism
Insulin increases facilitated diffusion of glucose
Insulin promotes hepatic glucose metabolism:
- increase in insulin:
> increase in glucokinase - increase glucose uptake
> increase glycogen synthetase - increase glycogen storage
- decrease in insulin:
> increased activity of liver phosphorylase - increased glycogen breakdown
> increase activity of phosphatase - increased glucose release
Insulin does not influence glucose metabolism in the brain:
- Brain cells freely permeable to glucose and utilise glucose as major energy substrate
describe glucagon and its action
Produced by pancreatic a-cells in islets of Langerhans
Secretion mainly stimulated by decrease in blood glucose
Counter-regulatory to the metabolic actions of insulin
it promotes hepatic glucose release:
- promotes glycogenolysis and gluconeogenesis
potent activation via cascade amplification
how is glucagon secretion regulated
secretion stimulated by:
- decrease blood glucose
- increase circulating amino acids
- exercise
secretion inhibited by:
- somatostatin - this has a general suppressive action on metabolism - extends period over which nutrients may be utilised
describe how hormones other than glucagon regulate carb metabolism
adrenaline/moradrenaline:
- α-adrenergic activation - increase glycogenolysis - increase blood glucose
- β-adrenergic activation - increase lipolysis by adipose tissue - more free fatty acids
cortisol:
- stimulation go hepatic gluconeogenesis - mobilisation of extra hepatic AAs
- decrease in glucose uptake in muscle and adipose tissue
- increase lipolysis by adipose tissue
growth hormone:
- increase hepatic gluconeogenesis
- increased lipolysis and fattu acid utilisation
- decrease tissue uptake of glucose
- increased protein synthesis
they all protect against hypoglycaemia
what is the difference between type 1 and type 2 diabetes
Type 1 Diabetes (~10 % of cases):
- insulin-dependent
- b-cell dysfunction
- viral infection, autoimmune, hereditary
- juvenile onset typically ~14 years
Type 2 Diabetes (~90 % of cases):
- non-insulin dependent
- insulin resistance
- obesity-related
- adult onset typically >30 years
name some adverse effects of hyperglycaemia
- tiredness
- frequent urination
- sudden weight loss
- wounds that won’t heal
- always hungry
- blurry vision
- numb or time;ing hands or feet
- always thirsty
describe glycosuria
Normally all filtered glucose reabsorbed in proximal tubule via SGLT1/2 cotransporters and GLUT2 transporters - resulting in return of glucose to circulation
- if renal threshold go approx 10mmol/L is reached then the proximal tubule is overwhelmed and excess glucose is excreted in the urine
- gliflozins are a drug that decrease renal glucose reabsorption and therefore decrease blood glucose
describe glucotoxicity
more glucose = more reactive oxygen speicies
- reacts with or alters proteins e.g. advanced glycation end-products (AGE), glycated haemoglobin (HbA1c)
- aberrant cellular messaging
- chronic inflammation
- b-cell dysfunction
- endothelial dysfunction
- TISSUE DAMAGE
describe the consequences of the switch to fat metabolism in uncontrolled diabetes
- increased hormone-sensitive lipase (inhibited by insulin) causes increased lipolysis
- this means more free fatty acids taken up bu the liver - this leads to B-oxidation to form ketone bodies (acetoacetate, β-hydroxybutyrate) both of these are acidic - decrease in blood pH and causes metabolic acidosis or diabetic ketoacidosis
- build up of H ions compete for binding sites on proteins with potassium (K+) - this means potassium is displaced and leads to hyperkalaemia
describe the effect on body protein in uncontrolled diabetes
less insulin means an increased utilisation of protein and fat for energy - this leads to a depletion of body protein
therefore untreated diabetes can lead to:
- rapid weight loss - asthenia (lack of energy) - polyphagia (increased appetite) - severe tissue wasting
describe the diagnosis of diabetes mellitus
Urinary glucose:
If blood glucose > ~10 mmol/L, glucose as > renal capacity for reabsorption
Fasting blood glucose and plasma insulin:
- Normal blood glucose: 3.4-6.2 mmol/L
- Normal plasma insulin: ~10 mU/mL (if doing this you can tell T1 vs T2)
Glucose tolerance test:
Delayed decreased of blood glucose after oral bolus
- either decreased insulin or decreased insulin sensitivity
Ketoacidosis:
decreased insulin signalling - more FFAs - β-oxidation - acetoacetate - acetone
Explain the role of amino acids in protein metabolism
Proteins largely absorbed as amino acids via 2o active transport
Only small quantities absorbed at any one time as slow digestion
Circulating amino acids are taken up by cells within 5-10 minutes
Low circulating concentrations; high protein turnover between cells/tissues
Amino acids actively reabsorbed in proximal tubules - normal conditions = no amino acid in urine - if protein in tubules exceeds amount then well start seeing protein in the urine
amino acids can be converted into a wide variety of proteins with diff functions
describe the storage of amino acids
Free amino acids cannot be stored
need to be converted to peptides, poly peptides and then intracellular proteins
- circulating amino acids usually v low
- due to reverse equilibrium od proteins
- amino acids stored in form of intracellular proteins - if needed there broken down by enzymes and go into the blood
- maintains low levels of circulating AAs but also means there’s a constant availability
most is stored in the liver but also in kidney and intestinal mucosa
cell has limit to amount of protein stored
excess amino acids used immediately for energy to converted to fat/glycogen
describe transamination
synthesis of non-essential AAs from essential AAs
Depends on formation of appropriate α-keto acids which act as precursors
Transamination – amino group transferred from amino acid to form α-keto acid
describe the use of proteins as a source of energy
Limit to the amount of protein that can be stored by each cell
Excess amino acids immediately degraded by liver starting with deamination due to activation of aminotransferases
Refers to removal of amino groups from amino acids, occurs by transamination
involving reverse process to that related to synthesis of amino acids - deamination is essentially the reverse of transamination
describe energetic utilisation of deaminated amino acids
Gluconeogenesis – some products of amino acid deamination (eg. α-ketoglutarate)
can enter TCA cycle and produce glucose
Ketogenesis forming acetyl CoA or acetoacetyl CoA which enters TCA cycle OR forms ketones
describe briefly how urea is formed by the liver
Ammonia released during deamination highly toxic - readily ionises to NH4+
- converted to urea which may then be excreted by the kidneys
Urea contains two NH2 groups
- one from NH4+ (carbamoyl phosphate)
- one from aspartate
Outline the hormonal control of protein metabolism
Growth hormone:
- Promotes synthesis of cellular proteins
- promotes AA membrane transport and RNA transcription/translation
Insulin:
- Promotes cellular uptake of amino acids, inhibits protein catabolism
- increases RNA transcription/translation, inhibits gluconeogenesis
- Lack of insulin - increased plasma AAs - energy/gluconeogenesis - muscle wasting
Testosterone:
- Growth hormone - continual muscle growth
- Testosterone - transient muscle growth
Oestrogen:
- minor muscle growth but insignificant versus testosterone
Thyroxine:
- increased cell metabolism - activation of anabolic/catabolic protein pathways
- less CHO/fat - increased protein degradation, adequate CHO/fat - increased protein synthesis
Glucocorticoids:
- increase protein breakdown, increase circulating AAs, increase hepatic and plasma proteins - increase gluconeogenesis
describe two in born errors of amino acid metabolism
Enzyme defects in the urea cycle
Deficiencies in enzymes involved in metabolism of AAs
Indicate how nitrogen balance is measured and conditions which may lead to positive or negative nitrogen balance
NITROGEN RELEASED DURING PROTEIN METABOLISM = NITROGEN EXCRETION
N-intake > N-loss = +ve N-balance (anabolic state)
N-intake < N-loss = -ve N-balance (catabolic state)
Measurement:
- Estimated by measuring dietary protein intake and urinary nitrogen over 24 h
List the types of lipids and their physiological importance
Outline the pathway of lipids from ingestion to utilisation in the tissues
Describe the types of lipoproteins and understand the differences between them
Understand the key factors in the regulation of blood lipid quantity
Understand what is dyslipidaemia and why it is a health risk
.
List the types of lipids and their physiological importance
1) Triacylglycerol/Triglyceride/neutral fat:
- carbon that’s part of the carboxylate group at the start of a fatty acid is the alpha
- carbon at the end of the fatty acid - part of a methyl group - is called an omega
- saturated - only contains single c-c bonds - meat and dairy
- unsaturated - contains at lest one c=c bond - mono contains only one double bond - mono is the healthiest fatty acid for you - poly saturated are less healthy than mono but still better than saturated fatty acids
- carboxylate group at one end and methyl group bath the other
- Membrane lipids:
- Phospholipids - 2 fatty acids bound to glycerol
- Sphingolipids - one fatty acid tail bound to sphingosine
List the types of lipids and their physiological importance
1) Triacylglycerol/Triglyceride/neutral fat:
- carbon that’s part of the carboxylate group at the start of a fatty acid is the alpha
- carbon at the end of the fatty acid - part of a methyl group - is called an omega
- saturated - only contains single c-c bonds - meat and dairy
- unsaturated - contains at lest one c=c bond - mono contains only one double bond - mono is the healthiest fatty acid for you - poly saturated are less healthy than mono but still better than saturated fatty acids
- carboxylate group at one end and methyl group bath the other
- Membrane lipids:
- Phospholipids - 2 fatty acids bound to glycerol
- Sphingolipids - one fatty acid tail bound to sphingosine
cholesterol:
- Precursor for synthesis – acetyl co A
- no fatty acids in cholesterol molecules - made up instead of parts of fatty acids so has similar properties
- steroid nucleus - 4 carbon hydrogen ring structures
- in the membrane - maintain fluidity of the membrane
- consumed in diet
- negative feedback to inhibit own synthesis
- cholesterol is esterized - cholesterol esters are its most efficient transport form
name some sources of fatty acids
- dietary fatty acids
- adipose tissue
- endogenously synthesised fatty acids
Outline the pathway of lipids from ingestion to utilisation in the tissues
- emulsified by bile
- degradation by lipases
- absorption and conversion into triacylglycerols
- incorporation into chylomicrons
what are lipoproteins
lipoproteins:
- Molecular complexes that consist of lipids and proteins. They function as transport vehicles for lipids in blood plasma.
- Lipoproteins deliver the lipid components (cholesterol and triglyceride etc.) to various tissues for utilization.
- Differ in the ratio of protein to lipids, & in the particular apolipoproteins & lipids that they contain
- Vary in size & density - as density increases size decreases - as triglycerides are removed from a lipoprotein the density increases
what are the functions of apolipoproteins
- Structural component of lipoproteins
- Enable transport of lipids
- Interact with cell surface receptors
- Activate/inhibit enzymes involved in lipoprotein metabolism
describe the size, major core lipids, origin and mechanism of catabolism of chylomicrons
see lipid metabolism lecture slide 13
size:
up to 1 um
major core lipids: dietary triglycerides (TGs)
origin:
intestine
mechanism of catabolism:
hydrolysis by LPL in tissues
describe the size, major core lipids, origin and mechanism of catabolism of chylomicron remnants
see lipid metabolism lecture slide 13
size:
30-50nm
Major core lipids:
dietary cholesteryl esters (ChEs)
origin:
chylomicrons
mechanism of catabolism:
receptor-mediated endocytosis in liver
describe the size, major core lipids, origin and mechanism of catabolism of very low density lipoproteins (VLDL)
see lipid metabolism lecture slide 13
size:
40-100nm
Major core lipids:
endogenous TGs
origin:
liver
mechanism of catabolism:
hydrolysis by LPL in tissues
describe the size, major core lipids, origin and mechanism of catabolism of intermetiede density lipoproteins (IDL)
see lipid metabolism lecture slide 13
size:
25-35 nm
Major core lipids:
endogenous TGs and ChEs
origin:
VLDL
mechanism of catabolism:
~50% receptor-mediated endocytosis in liver;
~50% conversion to LDL
describe the size, major core lipids, origin and mechanism of catabolism of Low density lipoproteins (LDL)
see lipid metabolism lecture slide 13
size:
18-28 nm
Major core lipids:
endogenous ChEs
origin:
IDL
mechanism of catabolism:
receptor-mediated endocytosis in liver or tissues
describe the size, major core lipids, origin and mechanism of catabolism of high density lipoproteins (HDL)
see lipid metabolism lecture slide 13
size:
5-10 nm
Major core lipids:
endogenous ChEs
origin:
intestine, liver
mechanism of catabolism:
receptor-mediated endocytosis in liver
describe the exogenous lipid pathway
see lipid metabolism lecture slides 15-17
Removal of chylomicrons from the blood - Plasma triacylglycerol and cholesterol transport
chylomicrons bind dietary triacyglycerols and cholesterol in the intestines
they are then transported in the blood
in the bloodstream chylomicrons bind to endothelium of capillaries of skeletal muscle and adipose tissue
enzyme lipoprotein lipase hydrolyses the triacylglycerols and free fatty acids are released into the tissues
what remains is a chylomicron remnant - containing mostly cholesterol - returns from the capillaries
chylomicron remnant makes its way to the liver and is taken up by liver by LDL receptors and dietary cholesterol is delivered
bile acids and cholesterol are delivered from the liver to the intestines
describe the endogenous lipid pathway
see lipid metabolism lecture slides 18-21
manufacture of lipids within the body itself and how those lipids are transported to peripheral tissues
VLDL are synthesised in the liver and they deliver endogenous triglycerides and cholesterol to the tissues
VLDL delipidated in capillaries by lipoprotein lipase - releases free fatty acids - taken up by cells of muscle and adipose tissue
glycerol backbone delivered to liver or kidney cells - to be converted to dihydroxyacetone phosphate
dilapidated VLDL emerge from capillaries as intermediated density liporoteins (IDL)
after degradation to IDL or LDL, about half are taken up by the liver via receptor-mediated endocytosis
tissues other than the liver take up cholesterol from LDL via LDL receptors
cholesterol removed from cell surface membranes by HDL - this cholesterol delivered to liver
describe reverse cholesterol transport
cholesterol removed from cell surface membranes by HDL - this cholesterol delivered to liver - process still poorly understood
describe how blood lipid levels are regulated
regulated by hormones
see lipid metabolism lecture slide 25
Insulin – promotion of fat synthesis and storage
promote mobilisation of fatty acids and depletion of fat reserves by promoting hormone-sensitive lipase: Stress hormones: - Adrenaline and noradrenaline - glucocorticoids (cortisol) - growth hormone
Cause mobilisation of fatty acids and depletion of fat reserves by accelerating metabolic processes:
- thyroid hormone
describe the use of triglycerides for energy
- Fatty acids enter the mitochondria
through carnitine cycle - Undergo b-oxidation
- Eventually acetyl-CoA is formed
- Glycerol is phosphorylated
into glycerol-3-phosphate - Enters the glycolytic pathway
- Eventually acetyl-CoA is formed
Almost all cells (exception: brain tissue and red blood cells) can use fatty acids for energy
what is dyslipidemia
what are its primary and secondary causes
Higher or lower than normal concentration of lipoproteins in the plasma specifically: ↑ Total Cholesterol (TC) ↑ LDL ↑ TG ↓ HDL
Causes:
Primary:
- genetic disorders
Secondary:
- diabetes
- nephrotic syndrome
- hypothyroidism
- drug induced
- hypertension
what are the main sites of calcium absorption, excretion and storage in the body
absorption: small intestine
excretion: kidneys
storage: bones
what are the normal plasma calcium levels
Normal plasma calcium levels are 2.35-2.55 mmol/L
two types:
diffusible and non-diffusible protein bound
within diffusible:
ionised (free calcium) and bound to anions
within non-diffusible:
bound to albumin and bound to globulin
what is the effect of pH on protein bound and free calcium
As pH decreases, H+ displaces Ca2+ from binding sites and the amount of iCa2+ increases.
Conversely, as the blood pH increases, albumin and the globulins become more negatively charged and bind more calcium, causing the amount of iCa2+ circulating to decrease.
what are some of the physiological functions of Calcium
see calcium intro lecture slide 7
- Bones and teeth
- Glycogen metabolism
- Protein secretion
- Plasma membrane integrity
- Coagulation
what is the action of parathyroid hormone (PTH) on bone kidney and intestine
also what are its regulators
Bone:
- Short-term: rapid exchange from bone pool to ECF
- Long-term: resorption (osteoclasts)
Kidney:
- reabsorption of Ca2+
- excretion of PO43-
- formation of 1,25-dihydroxycholecalciferol
Intestine:
- Ca2+ absorption
Regulators:
- Low calcium (Ca2+)
- High phosphate (PO43-)
describe the action of vitamin D on the intestine kidneys and bone
what are its regulators
Actions
- Intestine: enhances Ca2+ absorption
(increases Ca2+ transport proteins – calbindin-D proteins)
- Kidneys: facilitates Ca2+ absorption
- Bone: increases calcification & mineralisation
(essential for normal osteoblast differentiation & function)
Regulators of active form:
- PTH
- Low PO43-
what are the causes of Rickets & Osteomalacia
Osteomalacia - vit D deficiency in adults
Rickets - vit D deficiency in children
- Lack of dietary vitamin D &/or sunlight (UV)
- Malabsorption of fats
- Failure to form calcitriol (active vitamin D)– can be due to chronic renal failure
who are at risk of vitamin D deficiency
elderly and Those from minority ethnic groups with dark skin such as those of African, African-Caribbean and South Asian origin, because they require more sun exposure to make as much vitamin D
what is the regulator for calcitonin and what are its actions on bone and kidneys
Regulator:
- High Ca2+
Actions
- overall lowers blood calcium
- Bone: inhibits resorption
- Kidneys: increases Ca2+ excretion
what hormones other than calcitonin, vitamin D and PTH act on bone
GH, IGFs:
- Promotes positive Ca2+ balance
- Excess - gigantism
Thyroid hormone:
- Essential for normal bone maturation in utero
- Excess - osteoporosis
Glucocorticoids:
- Small amounts essential for normal bone development
- Excess – osteoporosis
Oestrogen & Testosterone:
- Increase bone formation
Prolactin:
- increased calcium absorption
what are the normal levels of calcium and the abnormal levels
Normal calcium ranges from 2.35-2.55 mmol/L
Abnormal calcium levels >3.5 mmol/L or < 1.9 mmol/L
what is hypocalcaemia, what are its causes and what are the clinical signs
decrease in serum calcium levels
Causes:
- Hypoparathyroidism - most caused by removal or accidental injury to parathyroid glands during surgery
- Pseudohypoparathyroidism - post receptor resistance to parathyroid hormone - target cells resistant
- Vitamin D deficiency - vit D needed for calcium absorption
Clinical signs:
- Hallmark is neuromuscular excitability followed by tetany - because calcium usually stabilises the RMP - can reach threshold more easily - involuntary skeletal muscle contraction which can be fatal
what is chvostek’s sign, what is a positive response and what does this show
elicitation - tapping on the face at a point just anterior to the ear and just below the zygomatic bone
positive response - twitching of the ipsilateral facial muscles, suggestive of neuromuscular excitability caused by hypocalcemia
what is trousseau’s sign, what is a positive response and what does this show
elicitation - inflating a sphygmomanometer cuff above systolic blood pressure for several minutes
positive response - muscular contraction including flexion of the wrist and metacarpophalangeal joints, hyperextension of the fingers, and flexion of the thumb on the palm, suggestive of neuromuscular excitability caused by hypocalcemia
what is hyperparathyroidism what are its causes and what are the clinical signs
increased serum calcium
Causes:
- Primary hyperparathyroidism - problem within parathyroid glands themselves
- Secondary hyperparathyroidism - the stimulus is low Ca2+
- Tertiary hyperparathyroidism - after long standing secondary hyperparathyroidism
Clinical signs:
- ‘Bones’: Bone pain
- ‘Stones’: Kidney stones
- ‘Groans’: GI disruption e.g. abdominal pain, peptic ulcer, lack of appetite, constipation
- ‘Moans’: CNS disturbance - depression of nerves, muscle weakness, lethargy, cardiac conduction abnormalities
