Metabolism and nutrition Flashcards
1
Q
How does glucose enter the cells?
A
Depend on the tissue;
Skeletal muscle -> insulin dependent.
Other tissues, diffusion gradient
Renal epithelium and GIT cells, move glucose using Na-Glucose transporters
2
Q
How does insulin promote glucose transport?
A
Insulin will increase the rate of glucose transport by about 10 x and control the rate of carbohydrates
metabolism in all cell types except brain cells and liver cells.
3
Q
what is the reaction carbohydrates undergo to produce energy
A
C6H12O6 + 602 = 6CO2 + 6 H2O + energy
4
Q
Glucose is “locked” into cells. How is this done, and in what tissues does this NOT occur?
why does this happen?
A
glucose enters the cells, it is phosphorylated to glucose-6-phosphate by the enzyme glucokinase in
liver cells, and hexokinase in most other cells. This
reaction is irreversible except in liver cells, renal tubular epithelium cells and intestinal epithelial cells that
possess the enzyme phosphatase that can reverse the reaction. When glucose is locked into cells it can be:
o Used directly to provide energy via glycolysis
o Store under the form of glycogen
5
Q
what is a broad overview of glycogenesis?
A
Glycogenesis: Glucose-6-phosphate ->
glucose-1-phosphate -> Uridine diphosphate glucose -> glycogen.
6
Q
what is the key enzyme which breaks glycogen down into glucose?
is it usuallty active/inactive and what modulates the functio of this ?
A
Phosphorylase
INACTIVE
Activated by epinepherine and glucagon
7
Q
How many ATP molecules are made from each glucose ?
A
38
8
Q
What is the net ATP gain from the hydrolysis of glycogen
A
2 moles of ATP
4 are made from the cycle, but 2 are also used by the cycle so the net gain is only 2
9
Q
what are the steps where ATP is generated in glycolysis?
A
1,3 biphophoglycerate -> 3-phosphoglycerate
▪
Phosphoenolpyruvate->pyruvate
10
Q
during hypoglycaemia, how does the body respond to ingrease BG?
A
Glucagon is releasd by α islets. Glucagon binds to G-pro -> increased cAMP - > glycogen is degraded into Glucose-1-phosphate -> glucose-6-phophate (via phophoglucomutase)-> dephosporilated by glucose-6-phosphate (G6P) producing 2 mole of ATP -> glucose -> released into the circulation down a concentration gradient
11
Q
what are the energy dependent rate limiting steps in glycolysis ?
A
The first one is hexokinase which
catalyzes the phosphorylation of glucose to glucose-6-phosphate (first step)
However;
The primary rate-limiting step in glycolysis is the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate, catalyzed by the enzyme phosphofructokinase-1 (PFK-1). This is more active at low ATP levels and vice versa
12
Q
what is the transition steps between glycolysis and krebs?
A
Pyruvate is made by glycolysis bound to coenzyme A -> acetylcoa + 2Co2 +4H
Acetyl-coa enters Krebs
13
Q
what is the overall role of the krebs cycle ?
A
It is a sequence of reaction where the Acetyl portion of acetyl
CoA is degraded to carbon dioxide, water, and H+ production.
Net reaction:
2 Acetyl-CoA + 6 H2O + 2 ADP –> 4 CO2 + 16 H+ + 2 CoA + 2 ATP
The H are bound to NAD and FAD
The goal of this is not to produce ATP but to produce NADH and FADH so that these can donate H+ in the ETC
14
Q
how much total energy is produced by glycolysis and krebs ?
A
2 ATP molecules during glycolysis
2 ATP molecules during the krebs cycle
15
Q
what are the main goals of glycolysis and krebs?
A
The main goal of the krebs cycle and glycolysis is not energy generation but rather creation of protons
which will then be used in oxidative phosphorylation. Hydrogens are released as sets of two and will then
bind to nicotinamide adenine dinucleotide (NAD+) according to the following equation:
16
Q
what is the goal of oxydative phosphorylation (aka ETC)
A
large quantities of ATP are being formed by oxidation of hydrogen via the process of oxidative phosphorylation. These enzymatic reactions occur in the mitochondria:
● Each hydrogen atom is split into a free electron and Hydrogen ions (H+)
● The electron will be used through the electron transport chain and H+ combined with oxygen to make
OH- and eventually water
17
Q
How is ATP produced in the ETC ?
A
As electron pass through the electron transport chain large quantities of energy are generated and used to pump
H+ ions into the intermembrane space. The H+ will then pass from the intermembrane space into the
mitochondrial matrix and the enzyme ATP synthase use this energy to convert ADP into ATP by adding a free ionic
phosphate radical.
18
Q
How much ATP is formed between glycolysis, krebs and ETc ?
show how much for each step
A
Glycolysis 2
Krebs 2
ETC 30 through NADh and FADh +4 from H entering at different points
19
Q
what are the cellular mechanisms that control glycolysis and glucose oxidation ?
A
● Effects of the concentration of ADP/ATP
● Citrate ions concentration
● Use of all the ADP/AMP
20
Q
How do cytrate ions control glucose utilisation for energy?
A
Produced by krebs, in high concentrations these will inhibit phosphofuttokinase preventing glycolysis
21
Q
How is ADP and AMP a rate limiter of glycolysis and krebs?
A
These are need to be phsophorylated to make ATP, so if you have used them all up, then you do not a substrate available
22
Q
How does an anaerobic environment affect energy metabolism ?
What is the defect and benefit of this?
A
It limits it as O2 is needed by the ETC and Krebs.
Low O2 -> pyruvate is made by glycolysis (does not need O2) -> lactic dehydrogenase converts pyruvate to lactate -> secreted into the curculation
This is very inneficient yielding insufficient ATP. However, as Lactate builds up, as soon as O2 returns, the lactate can be immediatelly re-converted to pyruvate +NAD and used in aerobic metabolism
23
Q
what is the pentose phosphate pathway ?
A
an alternative pathway for energy generation which ustilises carbs
Glucose enters the pentose phosphate pathway when it is converted into Glucose-6-phosphate producing 4H+, 1 crbon atom and D-ribulose (4 carbon sugar)
24
Q
why is the pentose pathway not the preferential pathway for energy generation ?
A
It is less efficient;
only 5 glucose molecule can be reformed from every 6 glucose molecule entering the pentose phosphate pathway.
25
what is a benefit of the pentose pathway ?
why?
It can be used to generate fat.
The hydrogen release during the pentose phosphate pathway does not bind to NAD+ but rather
binds to NADP+ (adenine dinucleotide phosphate). This differennce is very important because
only hydrogen bound to NADPH can be used to synthesize fat.
26
what is the role of glycogenesis?
Excess glucose can be converted to glycogen. Glycogen stors up to 12-24h of energy, primarily in the muscle and lier cells.
27
what is the role of gluconeogenesis ?
Why does this exist?
Fat, glycogen and AA can be used to generate glucose, when BG is low.
The brain and red blood cells need a constant supply of glucose between meals to function
properly. Additionally, becuase their glucose uptake is not energy dependent, they rely on the concentration gradient of glucose. If glucose in the blood is low, but not critical, you will still get a metabolic drop as the diffusion of glucose into the cells is slower than what it is normally
28
during fasting, what is the primary site of gluconeogenesis and glucogenlysis?
During fasting, glucose is made primarily from what molecules?
The liver is the primary site where glucose will be made from either glycogen stores
(glucogenolysis) or synthetized from amino acids and fat (gluconeogenesis)
25% of the glucose made by the liver during fasting is made via glucogenolysis & the rest is made from amino acids conversion
29
what proportion of AA can be converted to glucose?
Only about 60% of the amino acids can be made into glucose
30
what regulates gluconeogenesis?
Decreased levels of glucose and carbohydrates –> increase glucagon -> increase rate of gluconeogenesis
ACTH and glucocorticoids; fasting/low BG-> secrete ACTH -> adrenal gland secrete glucocorticoids -> protein break down so amino acids are made available to the liver for glucose synthesis and
31
what is apolipoprotein B
It is a apoprotein found on chylomicrons which increases their stability in the lymph
32
How are chylomicrons processed by the target cells
removed from the blood when they pass through capillaries of various tisues, especially adipose tissue, heart and skeletal mucles.
Tissue contains lipoprotin lipase (on endothelial cells) which hydrolyzes the chylomicron triglycerides into FA's and monoglycerides.
The free FA's migrate in the cell where they are ether used by gluconeogenesis to produce energy, or are made into tryglycerides again.
The remnats of the chylomicrons are now cholesterole enriched, They bind receptors on the liver sinuiods. Apoliprotein-E is key in carrying cholesterole into the liver cells and neurons
33
Free fatty acids in the blood are transported by what?
They bind to Albumin as a transporter molecule
34
how is adipose tissue mobilised for energy productio?
Triglycerides stored in adipose tissues are hydrolyzed back to free fatty acids and glycerol to be
transported. Two stimuli promote hydrolysis of triglycerides in adipose tissues:
▪ Decreased amount of glucose available for the cells: α-glycerophosphate, one of the break-down of glucose metabolism is in decrease quantity and is required to maintain glycerol. As a result of decrease quantities, free fatty acids are released from triglycerides.
▪ Hormone-sensitive cellular lipase – can be activated by varying hormones in the body
35
Hormone-sensitive cellular lipase is activated by which molecules hormoneS?
glucagon, catecholamines (like epinephrine and norepinephrine), cortisol, ACTH, and growth hormone. These hormones act through a signaling pathway involving cAMP and protein kinase A (PKA), which phosphorylates and activates HSL
36
what are lipoproteins and what types are there ?
Post-absorption most of the fat in plasma is found as low-density of lipoprotein which have basically the same structure as chylomicron. Lipoprotein contains varying degree of triglyceride, lipoproteins and phospholipids. These can be classified according to their composition:
(1) very low density lipoproteins (VLDLs)- contains high concentration of triglycerides, moderate concentrations of both cholesterol and phospholipids
(2) intermediate density lipoproteins (IDLs) – Basically a VLDLs from which a share of the triglycerides has been removed increasing the amount of cholesterol & phospholipids
(3) Low density lipoproteins (LPL) – Derived from VLDL from which all triglycerides have been removed leaving only cholesterol and phospholipids
(4) High density lipoproteins (HLP) – Contains high amounts of proteins (>50%)
37
what are the 4 different types of lipoproteins and what are their charachterists?
(1) very low density lipoproteins (VLDLs)- contains high concentration of triglycerides, moderate concentrations of both cholesterol and phospholipids
(2) intermediate density lipoproteins (IDLs) – Basically a VLDLs from which a share of the triglycerides has been removed increasing the amount of cholesterol & phospholipids
(3) Low density lipoproteins (LPL) – Derived from VLDL from which all triglycerides have been removed leaving only cholesterol and phospholipids
(4) High density lipoproteins (HLP) – Contains high amounts of proteins (>50%)
38
where are lipoproteins syntheisised?
they are all synthesised in the liver
39
what are the major functions of adipose tissue?
- storage of triglycerides
- Heat insulation
- secretion of hormones (leptin, adipodectin)
- These are specialised fibroblasts which contain 80-90% of their cell volume as triglycerides (stored in a liquid state)
- Metabolise triglycerides from chylomicron adn lipoproteins or split fatty acids to be taken into the blood
40
what is the livers role in lipid mtabolism?
▪ degrade fatty acids in compounds that can be used for energy
▪ synthesize new triglyceride from carbohydrates & proteins
▪ synthesize cholesterol and phospholipids from fatty acids
41
what happens to the livers composition during starvation/fasting?
Large quantities of fat are found in the liver in certain conditions (e.g., starvation, diabetes mellitus, any conditions where fat is used instead of carbohydrates for energy). In these conditions, large quantities of free fatty acids are released in the blood, redeposited in the liver as triglycerides where they can be degraded to provide energy. As a rule of thumbs, the amount of fat in the liver is highly dependent on how much the body relies on fat for energy.
42
How are triglycerides broken down for energy?
Break down triglyceride into free FA and glycerole
Glycerole -> glycerol-3-phosphate which will enter glycolysis
Free FA procesessed by the mitochondria -> enter via carnitine carrier -> combined with Acetyl-Coa -> undergo β oxidation where they from acetyl-coa. Acetyl-coa will then ether;
1) enter krebs -> oxidative phosphorilation
2) Be used to form acetoacetic acids (Acetoacetic acid, β-hydroxybutyric acid, acetone)
43
How many molecules of ATP are formed by the oxidation of one FA
146 ATP molecules
44
what is the purpose of the 3 acetoacetic acids?
what is the other name for these?
and what are the 3
These are ketone bodies
They are;
1) acetoacetic acid
2) β-hydroxybutyrate
3) Acetone
They diffuse out of the lover freely, into the blood, and are taken up by other cells which can reverse reaction back to acetyl-coa and then use them for energy
45
What is ketosis and give three conditions in which this occurs
Why does this occur?
1) diabetes melitius
2) starvation
3) Diet primarily made of fat
This is when Acetoacetic acid, β-hydroxybutyrate and acetate build up in the interstitial fluid and blood.
carbohydrate metabolism is essentially shut down. In Starvation or fat-rich diet, there is no carbohydrates available for glycolysis; in diabetes mellitus, the lack of insulin prevents entry of glucose into cells. This essentially forces the body to rely on fat metabolism for energy production.
46
What influences the RATE of fat mobilisation?
1) availability of carbohydrate
2) hormonal influence (glucagon, cortisol, lack of insulin)
47
if ketone production is a safety mechanism for energy production when there is a lack of carbohydrate, why do we get extreme acidosis from this?
Why is this important for diabetics
The utilization of ketones is limited by the availability of oxaloacetate which is a product of carbohydrate metabolism. Ketones are made into acetyl-coa, but they need to be bound to oxaloacetate in the krebs cycle. With no carb metabolism, oxaloacetate is depleted leaving ketons which cannot be utilised. these are acids, so pH drops. In diabetics, this is when we get DKA
48
How and why are carbs stored as fat ?
what are the key steps in this process ?
When carbohydrates enter the body in greater quantities that are needed for energy production and glycogen
storage, the remainder is stored as triglycerides.
Two spets
1) Acetyl-coa is converted to into FA's via Malonyl-Coa and NADPH
2) 14-18 carbon free fatty acids chain to glycerol to form a triaglyceride
| the glycerole is provided as a α-glycerophosphate
49
How efficient is the convrsion of glucose into triaglycerides?
How much of the carbohydrate energy is stored as fat, how much is lost and what is it lost as ?
85% of energy is converted, 15% lost as heat
50
what are the benefits of fat synthesis and storage?
- confers an ability to store energy as glycogen and fat, provide a mean to store energy for long term use
- Each gram of fat contains 2.5 x the amount energy contained in glycogen. Fat is much more
energy dense and lighter
51
How does the body determine whether it will produce free fatty acids or store excess glucose as tryglyceride?
Free fatty acids and triglycerides are in a state of constant equilibrium. When there is excessive carbohydrates break down it produce α-glycerophosphate which will bind free fatty acids to form triglycerides therefore shifting the balance toward fat storage
52
what is the first rate increasing step in the production of fat ?
Formation of Acetyl-Coa-> Manolyl-Coa. This is formed by the enzyme Acetyl-coa-carboxylase which affiniy is increased in the presence of intermediates from the Krebs cycle (aka when there is increased carbohydrate metabolism)
53
what hormones regulate fat utilization and how?
- Decrease insulin; lack carbohydrates decrease rate of fat storage
- Epinephrine & norepinephrine; adrenal medulla increases production during exercise or any sympathetic nervous system activation (stress). Acts on hormone-sensitive triglyceride lipase which is present in adipose tissue and causes oxidation of triglycerides to mobilize free-fatty acids
- Cortisol and ACTH will have the same effects and active the hormone-sensitive triglyceride
lipase. In conditions where excessive cortisol and ACTH are secreted (e.g., Cushing’s disease) fats are mobilized to such a great extent that ketosis results.
o Growth hormone has a similar but weaker effect to ACTH and cortisol
o Thyroid hormone – cause rapid fat utilization
54
why does cushings cause fat mobilisation
- Cortisol and ACTH will have the same effects and activate the hormone-sensitive triglyceride
lipase. In conditions where excessive cortisol and ACTH are secreted (e.g., Cushing’s disease) fats are mobilised and free FA released (causes liver swelling) by trygliceride lipase
55
why does stress cause fat mobilisaiton ?
- Cortisol -> activate the hormone-sensitive triglyceride lipase -> fats are mobilised -> free FA released (causes liver swelling) by trygliceride lipase
- Cortisol -> downregulates insulin sensitivity
- Epinephrine & norepinephrine; adrenal medulla increases production during stress and sympathetic nervous system activation. upregulates hormone-sensitive triglyceride lipase in adipose tissue causing oxidation of triglycerides to mobilize free-fatty acids
56
what are the 3 major phospholipids?
●Lecithins
●Cephalins
●Sphingomyelin
57
what are the major functions of phospholipids?
- major constituent of lipoproteins in the blood -> In the absence of phospholipids serious abnormality of transport of cholesterol and other lipids occur
- Thromboplastin which is essential to initiate the clotting process is compose mainly of cephalins one of the phospholipids.
- Sphingomyelin are important to act as an electrical insulator in the myelin around nerve sheath
- Phospholipids are donor of free phosphate radicals when needed for chemical reaction
- Phospholipids are part of the structural elements (mainly membranes) throughout the body
58
what is exogenous and endogenos cholesterole?
- exogenous -> diet absorbed
- Endogenous -> synthesised in the body, primarily by the liver
59
what is the structure of cholesterole and why is this important?
sterol ring which is made up of many Acetyl CoA molecules fused together. Depending on the side chain the sterol nucleus can be modified to make:
o Cholesterol
o Cholic acid which is the basis of bile acids
o Many important hormones secreted by the adrenal glands (steroids)
60
How will increased exogenous uptake of cholesterole affect endogenous formation, how and how will this effect blood plasma levels of cholesterole?
Exogenous ingestion of cholesterol will inhibit a key enzyme in the synthesis of cholesterol:
3-hydroxyl-3-methylglutaryl CoA reductase – thus increase of cholesterol ingestion will not
change the plasma concentration of cholesterol in the plasma.
61
How does exogenous cholesterole uptake affect blood cholesterole levels?
what are other factors which will cause it to change?
Increased exogenous uptake will not affect cholesterole levels as the increased uptake inhibits 3-hydroxyl-3-methylglutaryl CoA reductase from making more endogenous cholesterole.
Things that will increase blood cholesterole level are;
- A diet in high saturated fat will increase blood concentration of cholesterol
- A diet in unsaturated fat will decrease blood concentration of cholesterol
- Lack of insulin or thyroid hormones will increase the blood cholesterol concentration – likely by decreasing the overall rate of fat utilization
- Genetic disorders – A defect in the LDL receptors may prevent cholesterol removal from the blood
62
what fat products are essential for cell and organelle membrane integrity
Phospholipids and cholesterole
63
what is the pathogenesis of artherosclerosis?
Fatty deposits (eventual plaque)
develop on the inside surface of the arterial walls.
-> Increase expression of adhesion molecules on the surface of the endothelium
-> Decrease the release of nitric oxide
-> exposed endothelium
Monocytes and lipids (mostly LDLs) will accumulate at the site of injury. Monocytes migrate into the vessels wall digest the lipoproteins -> The macrophages stay aggregated in the vessel wall and form a fatty strict-> The
macrophages release inflammatory mediators which cause further progression of the fatty strict -> Eventually the
fatty plaque can start bulging into the lumen of the vessels greatly reducing its circumference-> The migration of fibroblast will cause the artery to become progressively more stiff.
Eventually, atherosclerosis can cause:
- Vessel rupture
- stenosis
- Thrombosis of a rupture plaque and blood clot formation
64
what are risk factors for high colesterole?
High risk facotors;
- Low density lipoproteins (LDL) – high blood concentration of LDL will increase the risk of
atherosclerosis especially when combine with obesity and lack of physical activity.
- Familial hypercholesterolemia – In animals with defect of the LDL receptors, the liver cannot
uptake LDL and continues to secrete cholesterol regardless of feedback mechanism
Other
- Obesity and physical inactivity
- Diabetes mellitus
- Hypertension
- Hyperlipidemia
65
what molecule is an engdogenous inhibitor of high colesterole?
High density lipoproteins (HDL) – humans with high ration of HDL to LDL have a decrease
likelihood of developing atherosclerosis. Believed that HDL can absorb cholesterol crystals from the wall of vessels
66
How to minimise risks of arthrosclerosis?
- Healthy diet, physical activity, diet containing unsaturated fat and low cholesterol
- Maintain normal blood pressure and avoid hypertension
- Control blood sugar/insulin treatment if diabetes mellitus is present
- Avoid cigarette smoking
67
what are the features that all aminoacids have in common?
o An acidic carboxyl group (COOH)
o Nitrogen group (NH2)
68
what are positive and negative acute phase proteins ?
Examples
Acute phase proteins are those whose plasma concentrations change during inflammation. Positive acute phase proteins increase in concentration during inflammation, while negative acute phase proteins decrease.
Examples;
- positive acute phase proteins include C-reactive protein (CRP), haptoglobin, and serum amyloid A.
- negative acute phase proteins include albumin and transferrin
69
What are the costituents of proteins and how are these held together ?
How are such large molecules folded?
Amino acids are bind to each other by peptide bounds which are formed When the carboxyl group reacts with the nitrogen group:
R-COOH + NH2 – R’
--> R – CO – NH -R” + H20.
Some proteins are made
up of thousands of amino acids. Hydrogen bonding between Carboxyl and nitrogen bomb allows for protein folding and twisting.
70
AA are absorbed from food in the interstine. However, we do not see an increase in protein levels on blood work post most meals. Why?
o Absorption of amino-acids is extended over 2-3 hr.
o Amino-acids are quickly absorbed by cells, especially the
liver
71
How are proteins taken into the cell?
Usually as amino acids, although small peptides can also be absorbed.
These are uptaken by active transport
72
what happens when AA enter the cell
Rapidly converted to proteins (and stored), which can be broken down later for release when [blood] are low, or when AA needed by ribosomes etc.
The only proteins that are not broken down for utilisation are ribosomes, sturctural proteins and nucleous proteinx
72
when do you see proteinuria in normal individuals?
Diets really high in protein can exceed the renal re-absorbition limit.
73
what are the cells that are best at storing protein?
liver cells, intestinal mucosa, and renal cells (to a lesser extends).
74
what hormones control aminoacid release and protein metabolism?
o Increase formation of tissue protein: insulin, growth factor
o Decrease formation of tissue protein: Glucocorticoids
The amino acids and proteins exist in a state of reversible equilibrium. The aa levels are keps relatively constant outside of disease processes
75
what are the 3 major blood proteins?
what are their general roles?
where are these synthesised?
Albumin – provide colloid osmotic pressure in the plasma which prevent plasma loss from
capillaries. Also transporter molecules for thigs like FA's, drugs etc.
Globulins – are responsible for acquired and natural immunity
Fibrinogens – polymerize into long fibrin strands when the clotting cascade becomes activated
albumin, fibrinogen, and 50-80% of globulins are synthesized by the liver. Remainder of the globulins are made in the lymphatic tissue.
76
what is the reverse equilibrium of tissue : plasma protein?
plasma proteins and tissue proteins exist in a reversible equilibrium
o Ratio of tissue protein:plasma protein is relatively constant 33:1
77
How, where and when are priteins used for energy?
Liver
When ecess aa are available these are sused for energy (or when hormonal imbalance promote non glucose metabilism).
Deamination -> amino (NH3) is removed from the amminoacids by aminotransferase enzymes. This way pyruvate can be obtained from removing NH3 which can enter Krebs
78
what is the byporduct of utilising AA for energy and how is this dealt with?
H3N can be transfered to another substance y glatamic acid or converted to ammonia.
Ammonia is then converted to Urea in the urea cycle by the liver
2NH3 + CO2 -> Urea
79
what is hepatic encephalopathy?
Conditions affecting hepatic function (eg PSS, synthetic failiure etc) cannot produce urea. The leads ammonia to accumolate -> enters the blood travels to the brain. Some will be excreted by the kidneys
80
what are ketoacids?
Byproduct of AA deammination
(1) form a chemical substance that can enter the citric acid cycle
(2) the substance that enters the citric acid cycle is degraded in the same manner
acetyl-CoA is used with carbohydrates or lipid metabolism.
o Certain amino acids such as alanine can be turned directly into pyruvic acids which can be used as
part of carbohydrates or lipid metabolism
81
If some aminoacids are non essential, why do we still need to consume these in the diet ?
A certain amount of protein is always degraded into amino acids every day (~ 20-30 gram/day for humans). Therefore, it must be replaced from the diet
You can just make those individual ones if you have a deficiency
82
what hormones affect protein syntheis?
How
Growth hormone
- Effect: increase the synthesis of cellular proteins
Insulin
- Effect: a total lack of insulin will reduce protein synthesis to almost zero.
- Insulin accelerates the transport of amino acids into the cells
- Insulin promotes carbohydrates metabolism (glucose availability) which reduce the rate
of protein degradation
Glucocorticoids
- Increase the rate of protein break-down in most tissues
Testosterone
- Increase protein deposition, especially muscles
Thyroxine
- Increase metabolism of cells which will increase protein breakdown once carbohydrates and fat store are used
83
What are the 5 main roles of the liveR?
1) Filtration and storage of blood
2) Metabolism of carbohydrates, proteins, fat, hormones, and foreign chemicals
3) Formation of bile
4) Storage of vitamin and iron
5) Formation of coagulation factors
84
what is the regenerative capacity of the liver and induces regeneration ?
One lobe can regenerate the whole liver as long as there are no viral or bacterial complications
transforming growth factor-β and other interleukins secreted by
hepatocytes are pro-regenerative
85
what are the major functions of the liver in regards to;
- carbohydrate metabolism
- fat metabolidm
- protein metabolism
| 4 carb
3 fat
4 protein
In carbohydrates metabolism, the liver performs the following functions:
1. Storage of large amount of glycogen
2. Conversion of galactose & fructose into glucose
3. Gluconeogenesis
4. Formation of many intermediate compounds from carbohydrates metabolism
In fat metabolism, the liver performs the following functions
1. Oxidation of fatty acids to provide energy for other bodily functions
2. Synthesis of large quantities of phospholipids, cholesterol, and lipoproteins
3. Synthesis of fat from proteins and carbohydrates
In Protein metabolism, the liver performs the following function
1. Deamination of amino acids
2. Formation of urea and removal of ammonia from the body fluids
3. Formation of plasma proteins
4. Interformation of different amino acids
86
Outside of the main roles with fat, carbs and protein, what are the roles of the liver in storage and metabolism?
- Storage site for vitamins (e.g., vitamin A, Vitamin D, Vitamin B12)
- Storage for iron as ferritin -> Hepatocytes contains large amount of apoferritin which is capable to combine reversibly
with iron. When iron is high in the blood it is combined to apoferritin and stored as ferritin. If iron blood levels are low ferritin is broken down and iron is released.
- Liver form substance responsible for coagulation
- Vitamin K is used by the liver to form prothrombin and factor VII, IX, and X
- Liver remove excessive drugs/hormones and excessive substances from the body
87
how is iron stored and released by the liver?
Hepatocytes contains large amount of apoferritin which is capable to combine reversibly
with iron. When iron is high in the blood it is combined to apoferritin and stored as
ferritin. If iron blood levels are low ferritin is broken down and iron is released.
88
what changes with synthetic liver failiure do you see on bloodwork ?
Low proteins (esp albumin), decreased urea, prolongation of PT/APTT, decreased BIL, HYPOglycaemia (downregulation of gluconeogenesis etc)
89
how long do RBC's last in dogs and cats and where are these broken down?
what is released during breakdown?
Dog 110-120 days
Cat 70-80 days
Reticuloendothelial system (spleen and liver) macrophages remove RBC and broken down into;
- Globulin
- Heme -> further broken down into;
1) free iron -> binds transferrin for transport in the blood
2) four pyrrole nuclei -> metabolised to biliverdin and then unconjugated to bilirubin -> billirubin is released by macrophages where it binds albumin in the blood steam
90
describe bilirubin metabolism?
Macrophages of the reticuloendothelial system phagocytose fragile RBC and then hemoglobin is broken down into:
- Globin
- Heme (further broken down)
1) Free iron – transported in the blood by transferrin
2) Four pyrrole nuclei, which are metabolized to biliverdin and then reduced to bilirubin (unconjugated)
Bilirubin is released by the macrophages and binds to albumin. The free bilirubin is taken in by the liver and hepatocytes will conjugate bilirubin with glucuronic acid to form bilirubin glucuronide (80%) & sulfate to form bilirubin sulfate (Together these are referred to as conjugated bilirubin).
Conjugated bilirubin is secreted into the intestines. In Intestines, conjugated bilirubin is turned into urobilinogen by bacterial action.
From this there are 3 options:
1) Urobilinogen can be reabsorbed into the blood and enters enterohepatic circulation
2) Be converted into stercobilin and excreted to the feces
3) Be converted into urobilin and be excreted in the urine
91
why do patients with liver disease at times turn yellow?
When bilirubin concentration in the extra-cellular fluid becomes > 2 mg/dL the tissue will physically appears yellow to the naked eyes (jaundice). This can be due to accumulation of either conjugated or unconjugated bilirubin.
92
what are causes of hyperbillirubinemia?
Is the billirubin mostly conjugated or unconjugated?
1) Pre-hepatic – due to hemolysis of red blood cells
- In cases of hemolysis, the ] destruction of red blood cells produces so much bilirubin that the liver cannot conjugate bilirubin fast enough for excretion.
- -> most billirubin is UNconjugated
2) Post-hepatic -due to obstruction of the biliary tree -> most conjugated
3) Hepatic – due to functional liver failure -> most conjugated
93
what is the van den Bergh reaction
test to differentiate conjugated vs unconjugated billirubin
If a red colour develops immediately it is called a direct positive. It happens if conjugated bilirubin is present. In an indirect positive test, the patient's serum is first treated with alcohol and later mixed with diazo reagent. This causes development of a red colour. It is seen if unconjugated bilirubin is present. If both conjugated and unconjugated bilirubin are present the reaction is termed a biphasic reaction
## Footnote
t involves mixing a serum sample with a diazo reagent, which reacts with bilirubin to produce a purple-colored compound called azobilirubin. The speed and intensity of the color development help distinguish between the two types of bilirubin
94
1g of carb, fat and protein = how many Kcal?
4 Kcal for carbohydrates
9 Kcal for fat
4 Kcal for proteins
95
what is a food with partial proteins?
protein are deficient in certain amino acids and cannot be used to replace the degraded
proteins from the body.
E.g., Corns has inadequate amount of trypsinophan & Lysine. It would need to be complemented with another proteins to provide all essential amino acids requirement for the body.
96
How do you determine the metabolic utilization of fat, carbohydrate, or proteins ?
Respiratory quotient – the ratio of carbon dioxide production to oxygen utilization can be used to
estimate fat & carbohydrates utilization
- When carbohydrates are used, one molecule of CO2 is produced from any one molecule of 02 used. The respiratory quotient is 1.0
- When fats are used. The respiratory quotient is 0.7
- When proteins are used. The respiratory quotient is 0.8
97
what are the brain regions that control hunger and satiety?
lateral hypothalamus nuclei serve as the feeding center and
excitation of this area will lead the drives for food search
ventromedial nuclei of the hypothalamus serve as the satiety center and can inhibit the feeding center.
The arcuate nuclei are the sites where multiple hormones released from the GI tract and adipose tissue converge to regulate food and control energy expenditure.
98
what are the two types of substance clases that have effect on the feeding center?
The hypothalamus has high density receptors for neurotransmiters and hormones.
Depending on their effect on the feeding center they can be classified as
- Orexigenic substances – that stimulate feeding
- Anorexigenic substances- that inhibits feeding
99
The arcuate nucleous has two types of neurons. Which are they and what do they do?
1) Pro-opiomelanocortin – (POMC) neurons that produce α-melanocyte-stimulating hormone (α-MSH) together with cocaine and amphetamine related transcript (CART)
2) Neurons that produce the orexigenic substances neuropeptide Y (NPY) and Agouti related protein (AGRP)
- Activation of POMC neurons: decrease food intake and increase energy expenditure
- Activation of NPY/AGRP neurons: increase food intake and decrease energy expenditure
These neurons are the targets of the main hormone/neurotransmitters that regulate appetites (e.g., leptin, insulin, cholecystokinin, and ghrelin).
100
How fo POMC neurons function?
produce ** α-melanocyte-** stimulating hormone (α-MSH) which then acts on **melanocortin**
**receptors** especially found in neurons on the **paraventricular** nuclei. There are 5 types of receptors but the main one are **MCR-3** and **MCR-4**.
- Activation of melanocortin receptors 3 & 4 reduce food intake and increase energy expenditure
- Inhibition of melanocortin receptors 3 & 4 increase food intake and decrease energy expenditure
101
why is anorexia often seen in cancer patients?
Tumours can activate MCR-4 receptors ( inflammation) can lead to anorexia.
MCR-4 is the melanocortin receptor bound by α-melanocyte which is secreted from anorexigenic POMC neurons
## Footnote
a mutation in this has been associated with obesity in humans
102
what is an endogenous POMP neuron inhibitor
AGRP (Agouti related protein) inhibits MCR-3 and MCR-4 POMC receptors. This inhibits the binding of α-melanocyte-stimulating hormone (α-msh) rpoduced by POMC causing an increase in appetite
103
why will an animal that has been starved eat a far greater meal than one whic has recently eaten ?
Glucostatic theory of hunger regulation – when blood glucose decreases it leads to an
increase in hunger
Similar effects have been shown to take place when amino acids and lipid concentration
decrease
104
how does blood [glucose] regulate hunger?
A rise in blood sugar will decrease the rate of firing of **glucoreceptors neurons** in
the satiety center in the ventromedial and **paraventricular** nuclei of the hypothalamus which **inhibits** the **feeding center**
A **drop** in blood **sugar** will **increase** the rate of **firing** of **glucosensitive neurons**
105
what is the effects of temperature on feeding and why?
the temperature center interacts with the feeding center. In general, cold temperature stimulates feeding while high temperature inhibits feeding (need fat for insulation when cold and you need more heat generation)
106
How does body fat affect hunger?
Adipose tissue produce **leptin**. An increase in the amount of adipose tissue leads to increase in leptin secretion. Leptin will interact with multiple neurons in the hypothalamus especially neurons of the arcuate nuclei: **POMC** neurons + **AGRP**/**PY** neurons.
Stimulation by leptin will initiate multiple action that decrease fat storage;
- Decrease production of appetite stimulator in the hypothalamus such as NPY and AGRP
- Activation of the POMC neurons, release of α-MSH, and activation of the melanocortin receptors
- Release of substances which decrease food intake
- Increase sympathetic activity to increase metabolic rate
- Decrease insulin secretion by pancreatic beta cells
107
what are recognised genetic causes of obesity
- POMC MCR-4 receptor mutation
- Congenital leptin deficiency
- Congenital mutation of the leptin receptors
108
what are the 4 causes of obesity
- decreased activity
- overnutrition/overeating
- Genetic mutations
- neurologic abnormalities
109
what is inanition, anorexia, cachexia?
Inanition is the opposite of obesity and is characterized by extreme weight loss. It can be caused by starvation or pathophysiological conditions that cause decrease in the desire for food.
Anorexia – is defined as the decrease in food intake due to decreased desire for food.
Cachexia – is the metabolic disorder caused by increase in energy expenditure due to pathological conditions. It causes weight loss that is greater than the reduction of food intake alone.
110
with systemic disease, what factors contribute to cachexia and/or anorexia?
IL-6, tumor necrosis factor-α, proteolysis inducing factor, IL-1β
interact with the melanocortin system and cause anorexia/cachexia (i.e. stimulaes anorexigenic) neurons
111
what is starvation and what pathways are used for energy generation?
ody has enough carbohydrates to supply energy for about ½
a day.
1) carbohydrate stores used first
2) proteins undergo depletion through 3 stages
1) rapid phase of depletion -> easily mobilised protein used i gluconeogenesis
2) after a few weeks gluconeogenesis falls to 30-50% of its previous rate. Fat mobilisation hastened and β-hydroxyburtyrate is prodominantly sysnthesized by ketosis -> alows for energy generation preserving remainder of protein stores
3) Fat stores are deplete and body re-enters rapid protein breakdown.
Once 1/2 of the protein store is depeleted patient will die
112
what occurs with vitamin metabolism during starvation?
the body will decrease stores of water-soluble vitamin (Vitamin B group and C) over a week leading to mild vitamin deficiency.
ADEK are not properly absorbed if there is not enough fat in the diet, and as body fat goes down, storage of ADEK is depleted
113
what are the B vitamins
Thiamin = Vitamin B1
Riboflavin = Vitamin B2
Niacin = Vitamin B3
Pantothenic acid = Vitamin B5
Pyridoxine = Vitamin B6
Biotin = Vitamin B7
Folic acid = Vitamin B9
Cobalamin = Vitamin B12
## Footnote
the race neatly professionally performed by F1 crews
114
The liver is a major store for which fat soluble vitamins ?
A and D
115
what are common features of vitamin's B
Essential for all animals and cannot adapt to deficiency in vitamin B
All vitamin B are water soluble
Vitamin B groups are all enzymes-co factors and 7 of them are used in energy metabolism
A lot of vitamin B deficiency will have similar signs: weight loss + lack of appetite
116
what is vitamin B1 and key points
Thaimine
- function; Co-enzyme in oxidative decarboxylation of α-ketoacids. Pyruvic acids cannot be converted to Acetyl CoA without thiamin
- deficiency; Metabolic acidosis as pyruvic acid is converted into lactic acids, Citric acid cycle is blocked which leads to ketone body production -> Failure of energy supply to the cells of the nervous system (neurological signs)
117
what diets are rich in B1 ? and what shoudl be avoided?
all cereal, muscle, liver and kidney contain B1
Raw fish contains a
lot of thiaminase which degrades vitamin B1 and can lead to deficiency -> esp in cats
118
what is vitamin B2 and key points
Riboflavin;
- Function; converted into FAD and FADH and FMN -> key for Beta oxidation of fatty acids, Citric acid cycle, Involved in energy production in mitochondria
- Deficiency; severe arrhythmias and CNS seigns (phenotiazine drugs acan cause a secondary deficiency
119
What is vitamin B3 and key points?
Niacin
- Function; needed for NAD formation ->It will be necessary for glycolysis, β-oxidation, citric acid cycle, electron transport chain
- Deficiency; Pellagra or Black Tongue Disease - dermatitis, dementia, diarrhea (tongue will be black with disruption of the oral mucosa)
120
what is vitamin B6 and key points?
Pyridoxine
- Function; involved as a co-factor in reactions where amino acids are being modified -> decarboxylation, transamination, and oxidative deamination
- Deficiency; Non-specific: weight loss, loss of appetite, Anemia ( microcytic hypochromic anemia)
121
what is vitamin B5, key pointS?
Pantothenic acid
- function; Ultimately, made as the coenzyme A – involve in all pathways responsible for energy
metabolism (Citric acid cycle, glycolysis, beta oxidation, etc…)
- Deficiency; rare as it is present in most foods
## Footnote
5 year olds like pantomines
122
what is vitamin B7 and key points?
Biotin
- Function; involved in carboxylation reaction where a CO2 is incorporated into organic molecule (e.g., gluconeogenesis)
- Deficiency: rare as it is present in most food items and gut bacteria can make this. Secondary deficiency – can occurs if animals treated with a sulfa drug or an animal fed
on raw eggs (avidin present in raw eggs bind to biotin)
Clinical signs – all related to the skin (Dermatitis & loss of hair)
123
Vitamin B9 key points?
Folic acid
- Function; Synthesis of purine nucleic acids (adenine & guanine)
- Deficiency; Failure of mitosis. Appetite loss, anemia, diarrhea (failure of mucosal cells to turnover properly)
124
Vitamin B12 key points?
Cobalamin
ONLY MADE BY YEAST AND BACTERIA
- Function; involved in the methylenation of folic acid and is necessary for cell division (red blood cells and enterocytes)
- Deficiency; Pernicious anemia (chronic non-regenerative anemia), Wasting & diarrhea
## Footnote
what fucks vegans over
125
describe the absorbtion of cobalamin
Cobalamin is bound to dietary protein and cannot be aborbed as is.
When it enters the stomach, dietary proteins are digested by
pepsin and HCl leading to release of free cobalamin. It is
immediately bound to R-protein (cobalamin transporter protein)
which is synthetized by the gastric mucosa. The R- protein –
cobalamin complex is enter the duodenum where R-protein is
digested by pancreatic enzymes. The free cobalamin is then
bound by intrinsic factor. In small animals, the majority of the
intrinsic factor is secreted by the pancreas. The complex of
intrinsic factor – cobalamin is then absorbed into circulation by
specific receptors found in the ileum.
126
what can affect cobalamin absorbtion ?
Severe distal small intestinal disease will cause destruction of
cobalamin receptors which eventually leads to deficiencies.
Exocrine pancreatic insufficiency is also a common cause of cobalamin deficiency due to lack of production of intrinsic factor
Small intestinal dysbiosis can also lead to cobalamin deficiency as certain bacterial species will
compete for cobalamin.
127
Vitamin C key points?
Ascorbic acid
Animals can synthetize Vitamin C from glucose except for primates and some small mammals (e.g., humans, guinea pigs, etc…)
- Funciton; Important in formation of collagen and elastin in the extracellular matrix (allows the hydroxylation ofproline to hydroxyproline) and Steroidogenesis (formation steroid hormones)
- Deficiency; Scurvy – because structural properties of collagen and elastin are damaged/incomplete the extracellular matrix does not hold together. This can leads to multiple hemorrhage, vascular fluid leaking out (edema), and animals becoming very emaciated.
128
Vitamin K key points?
Can be absorbed from animal proteins or made by animal from carotenoid. This reaction occurs
in the small intestinal mucosa. Vitamin A is going to be stored in the liver.
Function;
- Vision -> retinol is converted to retinal which can bind the opsin protein forming rhodopsin. When rhodopsin interacts with light in dissasociates to retianl+opsin which is what allows the retina to detect light
- systmeic; Retinol is converted to retinoic acid which regulates gene expression. This is particularly important in epithelial cells differentiation
Deficiency;
- night blindness
- severe damage to epitherlial cells of the GIT, respiratory and urinary mucosa)
- Keratin metaplasia -> viatmin A helps regulate keratin growth and causes compression of nerves traveling through the foramien
- abortion and infertility
Toxicity; Ankylosing spondylitis - Large amount of vitamin A cause overgrowth of the periosteum
which will cause fusion of different joint of the spine. This eventually leads to varying
degree of immobility. The condition was noted in cats fed entirely on beef/sheep liver.
129
what does vitamin A tox casuse
Toxicity; Ankylosing spondylitis - Large amount of vitamin A cause overgrowth of the periosteum
which will cause fusion of different joint of the spine. This eventually leads to varying
degree of immobility. The condition was noted in cats fed entirely on beef/sheep liver.
130
Vitmain D synthesis ?
cholecalciferol
Vitamin D is made from cholesterol and is made by photosynthesis in skin when it is exposed to UV light.
Cholecalciferol is made in the skin and will travel in the blood bond to vitamin D binding protein (DBP). It will be stored in the liver and undergo one transformation to get a hydroxyl group at the end of the amino acid chain to be become 25-hydroxy-cholecalciferol. Once it undergoes this change it re-enter circulation. In the kidneys, it can undergo another hydroxyl group one carbon one to become 1,25- hydroxy-cholecalciferol which is the functional form of vitamin D.
131
what animals cannot synthesis vitamin D from UV light ?
feline, vampire bat, fishing bat
132
what is the function of vitamin D ?
what happens during deficiency and toxicity ?
Calcium homeostasis;
- 1,25-hydroxy-cholecalciferol stimulate gene expression on the cells of the intestinal mucosa allowing for increased calcium absorbption
- Increases osteoclast release of Ca
- increases renal reabsorbtion of Ca
Deficiency
- bone loss
- joint swelling
toxicity
- hyepercalcaemia and acute renal failiure
133
Vitamin E key points?
α-tocopherol
It is absorbed in conjunction with dietary fat and is transported into the liver.
o Function:
- Act as a physical component of cell-membranes to provide flexibility and fluidity.
- Act as an antioxidant – this bind to free radicals OH- to prevent them from grabbing
hydrogen atoms from membranes and organelles. This provides oxidation of
unsaturated fat.
o Deficiency:
- all can be explained by free radical damage
- Fetus resorption
- Necrotizing myopathy – muscle cells dies and are replaced by connective tissue
- Anemia
134
Vitamin K key points?
here are two form of vitamin K : vitamin K1 phylloquinone (made by plant) and vitamin K2
menaquinone (made by bacteria)
o Function: involved in blood clotting
o Deficiency: deficiency in vitamin K -dependent clotting factors, bleeding
135
Magnesium key points?
is required as a catalyst for many enzymatic reactions, especially those involved in carbohydrates metabolism
o ↑ extracellular Mg leads to depression of the central nervous system, weaken muscle contraction
o ↓ extracellular Mg leads to irritability, vasodilation, arhytmias
136
why is zinc essential?
this is an integral part of the enzyme carbonic anhydrate
137
what is oxygen debt?
The concept of oxygen debt – After exercise, the oxygen consumption continues to be high and is used to;
▪ Reconvert lactic acid into glucose
▪ Reconvert ADP into ATP
▪Reconvert creatine & phosphate into phosphocreatine
▪Re-establish the concentration of oxygen
▪Raise the concentration of oxygen in the lungs
138
how can you measure metabolic rate?
⇨Direct calorimetry measures heat liberates from the body
⇨Indirect calorimetry – measured the rate of energy liberated based on the amount of oxygen consumed.
For example, 1 L of oxygen consumed when using average body produce 4.825 Calories.
139
what is a calorie
calories with “a little c” reveal the quantity of heat required to raise the temperature of 1 gram of water by 10C
140
what is basal metabolic rate?
what factors can increase/decrease this?
the minimum amount of energy of the body required to exist. It will account for about 50-70% of the total energy output.
Factors that increase/change metabolic rate:
⇨Thyroid hormones will **increase** metabolic rate
o Thyroxine will increase the rate of chemical reaction in many cells. Maximal thyroid secretion may increase metabolic rate by up 50-100%.
⇨ Male sex hormone will **increase** metabolic rate
o Male sex hormones may **increase** metabolic rate by 10-15%
⇨ Growth hormone increase metabolic rate
⇨ Fever will **increase** metabolic rate
⇨ Sleep will **decrease** metabolic rate
o Due to relaxation of skeletal muscles
o Decreased activity of the central nervous system
⇨ Malnutrition **decreases** metabolic rate
141
what is the thermogenic effect of food?
After ingestion a meal the metabolic rate increases due to the energy released during the digestion, absorption and storage of food. As a whole energy expenditure due to food
consumption represent 7-8% of the total energy output
142
what is normal body temperature for dogs in cats in dumb unites (aka farenheit) ?
Dogs: 101-102.5 0F
Cats: 100.5 – 102.50F
143
How is body temperature controlled?
The body temperature is controlled by balancing heat production and heat loss
●When the rate of heat production in the body is greater than the rate at which the heat is being lost, heat builds up in the body
● When the rate of heat loss is greater than the rate of heart production, temperature decrease
144
why is fat essential in preventing heat loss ?
Fat allows heat transfer only at 1/3rd as effectively as other tissues
145
How is heat controll performd by the body?
| as in heat retention or increased loss
he skin is underlayed by venous plexus with multiple arteriovenous anastomosis. This system can receive as little as nearly 0% of the cardiac output or almost 30%. Heat conduction through the skin depends on the
degree of vasodilation of the artery supplying the venous plexus. This is controlled by the sympathetic nervous system in response to change in core and environmental temperature.
o If outside temperature cold, this will lead to severe vasoconstriction of that venous plexus and therefore reduces heat exchange
o If outside temperature hot, this will lead to severe vasodilation of that venous plexus, and there
increases heat exchange.
146
How is heat lost through the skin ?
radiation, conduction, evaporation and
convection.
Radiation; refers to heat loss in the form of infrared rays -> Without fur this would account for 50-60% of total heat loss. All object that are not at absolute zero temperature emit heats that way. It is at an equilibrium,
if the temperature of the body is higher than the outside environment, more heat is radiated from the body than to the body.
Conduction; refers to heat loss by direct contact with an object.
- Direct contact with object only account for 3-5% of the heat loss
- Heat loss through the air accounts for 10-15% of the heat loss.
It is minimal unless there is
constant movement of air that remove the hot air. This process is referred to as air convection.
Evaporation; refers to the loss of heat as evaporation of water
- Insensible evaporation – refers to the passive diffusion of water through the skin and lung
surface. This cannot be used in terms of heat control
- Evaporation of sweat can be controlled by controlling the rate of sweat. Evaporation is a
necessary cooling mechanism at very high temperature.
147
when the environmental temperature is above that of the body, which is the only way that the body can promote heat loss?
However, when the environmental temperature is above skin temperature evaporation is the only mechanism of heat loss.
148
How is sweat produced and regulated?
Sweating is regulated by the autonomous nervous system.
High environmental temperature will stimulate the hypothalamus. Hypothlamus -> spinal cord -> sympathetic nerves -> sweat gland subdermal coiled portion secreates swet -> sweat exits by the duct
Note
that the sweat glands have cholinergic fibers (secrete acetyl-choline) that run with
the adrenergic fibers of the autonomous nervous system.
The gland can be stimulated by epinephrine and nor-epinephrine even through they do not have
adrenergic innervation.
149
How is sweat produced and modified by the gland?
The deep subdermal coiled portion will first form a primary secretion which is mainly
a protein-free filtrate which is very similar to plasma. The collecting duct will mainly. cause absorption of Na+ and Cl- forming sweat. This rate of re-absorption is determined by the rate of sweating. In
a hot environment, the high rate of sweating decrease the rate of re-absorption of Na+ and Cl- which cause the
sweat to have higher concentration of Na+/Cl-
.
150
what is sweatting aclimatisation ?
the longer you spend in a hot place (>1-6 weeks) the aniybt and rate of sweat production will decrease.
Associated with acclimatization is the increase conservation of Na+/Cl- in sweat production. This is mediated by aldosterone.
151
Dogs and cats have minimal ability to sweat as they are fur covered and their skin lacks sweat gland; What do they do instead?
Instead, they have a panting mechanism. When the blood becomes overheated, the panting centers becomes activated. When the panting center is activated, there is rapid which causes large quantities of new air to come into contact with the respiratory mucosa. This results in increased evaporation from the respiratory mucosa and the
saliva present on the tongue.
152
How does the centrally body regulate heat ?
hypothalamus contains numerous heat sensitive neurons which function as temperature sensors.
- Heat sensitive neurons increase their firing rate in response to heat
- Cold sensitive neurons increase their firing rate in response to cold
The hypothalamo-preoptic area can serve as a thermostatic body temperature control center. When the
hypothalamic preoptic area is warmed it leads to:
- Profuse sweating/panting
- Systemic vasodilation
153
How does the body detect temperature throug the skin
The skin contains many warmth and cold receptors. The skin contains 10 x more receptor for cold compared to
warmth receptors. If the entire skin is chilled, it will lead to 3 actions:
-Strong stimuli to cause muscle shivering to ↑ heat generation
- Vasoconstriction
-Inhibition of sweat production
154
where are deep thermoreceptors and what are their roles?
Deep receptors are found in the spinal cord, abdominal viscera, and deep vessels and like the skin receptors are more concerned with hypothermia.
155
How does the brain respond to increased or decreased externa temperature?
he posterior hypothalamus will integrate signal from the anterior hypothalamus preoptic centers and peripheral
receptors.
●Temperature-decreasing mechanisms when hyperthermia sets in
o Vasodilation of the skin blood vessels-
o Sweating
o Decrease in heat production – the mechanism that produce heat are inhibiting (e.g., shivering and chemical thermogenesis)
●Temperature-increasing mechanism when the skin too cold
o Vasoconstriction
o Piloerection – hair in the body stand and entrap the hot air next to the skin
● Increase in thermogenesis –
▪Hypothalamic stimulation of shivering can increase heat production by 4-6 times.
▪ Sympathetic stimulation increases the rate of cellular metabolism, this is called chemical thermogenesis by causing uncoupled oxidative phosphorylation where excessive
foodstuff are oxidized without forming any additional ATP (major role of brown fat)
▪ Increased thyroxine output - Cooling of the hypothalamo-perioptic area cause release of
thyroid-stimulating hormones which increase thyroxine production by the thyroid gland.
This increases the rate of cellular metabolism and is another mechanism of chemical
thermogenesis. Long-term exposure to cold will cause thyroid glands to increase in size.
156
what are pyrogens?
Substances such as protein break down product or
lipopolysaccharides from bacterial wall can cause increase of the hypothalamic thermostat
157
what are the mechanisms of action of pyrogens?
- Endotoxins from bacteria can cause increase in temperature set-point
- Phagocytosed bacteria or damaged cells will cause release of IL-1 from macrophages which by itself is a potent pyrogen
158
when do we see gross lipaemia?
Gross lipemia occurs secondary to moderate to severe elevations in triglycerides (200 mg/dL)
159
what is the chylomicron test?
a serum sample, if creamy → cream layer in top indicated electaed chylomicrons or VLDL
160
what are the 3 types of lipid and the multiple names these have?
Triglycerides (acylglycerols)
Phospholipids
Cholesterol (sterols)
161
what is lipoprotein lipase?
where is it found and what does it do?
what activates this ?
| LPL
Located in luminal surface of endothelial cells in adipose tissue, skeletal muscle, heart
Promotes fat storage and
- Hydrolyzes triglycerides within lipoproteins → FFA, monoglycerides, diglycerides, glycerol that can then enter the tissue for storage (e.g., adipose) or energy use (e.g., muscle)
Activated by insulin & inhibited by glucocorticoids
162
what is hormone sensitive lipase?
where is it found and what does it do?
Intracellular in adipose tissue
Mobilizes lipid stores
Hydrolyzes stored triglycerides, diglycerides and monoglycerides → FFA for release back into circulation
Activated by glucocorticoids, glucagon, and epinephrine & inhibited by insulin
163
what is hepatic lipase?
Located in endothelial cells hepatic sinusoids, extrahepatic tissues
Uptakes triglycerides and phospholipids from chylomicrons and VLDL remnants
Converts VLDL → LDL
Converts HDL2 → HDL3
164
Dietary lipids reach the duodenum and undergo emulsification by_______
Lipases
165
FFA and monoglycerides → microvilli brush border and form ____, which diffuse through the epi cell membranes into mucosal cell
Micelles
166
Triglycerides combine with phospholipids, cholesterol and apolipoprotein to form _________
Chylomicrons
167
Chylomicrons (main transfer of lipid and triglyceride) → secreted into ____ → lymphatics → blood → acquire ____ and ____from HDL
Lacteal
Apo C
Apo E
168
Describe the exogenous pathway of lipid metabolism?
1) Dietary lipids reach the duodenum and undergo emulsification by lipases
2) FFA and monoglycerides → microvilli brush border and form micelles, which diffuse through the epi cell membranes into mucosal cell
3) Within the mucosal cell, monoglycerides and FFA to form triglycerides
4) Triglycerides combine with phospholipids, cholesterol and apolipoprotein to form chylomicrons
5) Chylomicrons (main transfer of lipid and triglyceride) → secreted into lacteal → lymphatics → blood → acquire Apo C and Apo E from HDL
6) Apo C activates LPL in capillary bed
7) FFA enter cells and/or adipocytes
8) Cholesterol rich chylomicron remnant → return to Apo2 and HDL → ApoE then stimulates removal from circulation by endocytosis in the liver
a. Used for VLDL, bile acid formation, cholesterol esters
169
what is Apo-C and Apo-E
Apolipoprotein C-III (ApoC-III) and Apolipoprotein E (ApoE) are both apolipoproteins that play crucial roles in fat metabolism, particularly in regulating the metabolism of lipoproteins like very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL). ApoE is involved in the clearance of these lipoproteins from circulation, while ApoC-III can influence their lipolytic processing and clearance
170
what is PLE pathophysiologically ?
what is a nutritional goal for these patients
| protein loosing nephropathy?
Characterized by excessive protein loss, malabsorption of chylomicrons
- Secondary inflammation/edema
Goal of ultralow fat diet:
- Decreased lymphatic pressure due to decreased fat absorption from mucosa
- <0.35-2 g/100 kcal
171
What are the main cholesterole carriers and triglyceride carriers ?
Exogous triglyceride carriers are the chylomicrons, while endogenous is VLDL
Cholesterole (only endogenous) are the LDL
172
Describe the endogenous pathway of lipid metabolism?
1) VLDL is formed by endogenously made triglycerides & cholesterol → combined with phospholipids
2) VLDL acquires Apo C and E from HDL in vasculature → activates LPL
a. VLDL triglycerides → FFA & glycerol → removed by liver OR LPL +/- hepatic lipase →LDL
3) LDL (contains cholesterol and phospholipids) → delivers cholesterol to tissues → used for synthesis of aldosterone, cortisol, androgens
4) HDL (synthesized in the liver) → acts as a donor and acceptor of Apo C/E
5) Reverse cholesterol pathway:
a. Cholesterol is transferred with small HDL → HDL3
b. HDL esterified → absorbed into larger HDL molecules → cholesterol rich HDL2
173
what is the cholesterole side chain cleaving enzyme?
Cholesterol side-chain cleavage enzyme rate limiting step of cholesterol to pregnenolone and further enzyme formation in the aldosterone, cortisol and androtestosterone pathways
P450scc (CYP11A1 → rate limiting step of cholesterol to pregnenolone
174
which hormones stimulate lipolysis?
Catecholamines
Norepinephrine
Cortisol
Glucagon
Growth Hormone
ACTH
175
Which major hormones inhibit lipolysis? How?
Insulin (via inhibition of hormone sensitive lipase [HSL])
176
Increased concentration of HDL and LDL → changes in serum ___________
cholesterole
177
what are the 4 major categories of hyperlipidemia?
What breeds re predisposed to hyperlypidemia and hypercholesterolemia ?
1) Postprandial (7-12 hours after a meal, recommend 15 hr fast, HTG>HCH) - BUT, generally mild unless eating a high fat diet
2) High fat diets (fat content must be >50%)
3) Primary hyperlipidemia (more than one subtype)
4) Secondary hyperlipidemia (more common than primary)
Hyperlipidemia -> miniature Schanuzer. Beagles can but more mild. These can both also get hypercholeesterolemia
Hypercholesterolemia ->shetland sheepdog. Mild HC can also be seen in doberman, rotweiler, briand, great pyreneese
178
List what endocronopathies cause hyperlypedemia and how?
Hyperadrenocorticism
- Increased cortisol concentrations → enhanced lipolysis, lipid mobilization, liponeogenesis and adipogenesis
Diabetes Mellitus
- VLDL & chylomicron breakdown by LPL is mediated by insulin → increase TG rich lipoproteins
- Altered hepatic triglyceride lipase (uptake of chylomicron/VLDL remnants containing ApoE)
Hypothyroidism
- Decreased cholesterol (ApoB containing), TG & LDL synthesis and degradation (Degradation>synthesis)
- Declined functioning LPL hydrolyzing VLDL & chylomicrons, decreased LDL clearance
- TSH is associated with increased cholesterol in humans
179
is pancreatitis caused by hyperlipedemia?
Historically thought to be a cause of secondary hyperlipidemia, but hyperlipidemia is uncommon and mild when present
Moderate to severe hypertrygliceridemia in a dog with pancreatitis is more likely a cause than effect
180
what association is there between renal disease and hyperlipedemia/cholesterolemia?
PLN and renal disease can develop nephrotic syndrome characterized by increased cholesterol +/- triglycerides (increased LDL & VLDL)
- Associated with prothrombotic risk
- High LDL and low HDL associated with platelet activation in people
Moderate to severe proteinuria is associated with an nicrease in tryaglicerides and cholesterole
181
what are secondary causes of dislipedemia?
Cholestasis
- Decreased biliary and therefore cholesterol clearance
Medications
- Phenobarbital: altered lipid metabolism, associated with obesity
- Prednisone: Similar to HAC
Obesity
- Mild to moderate elevations in HTG & HC possible with BCS of 8-9/9
182
why do dogs rarely get arthrosclerosis compared to humans?
DOGS:
- Carry most cholesterol in HDL (“good cholesterol”)
- Lack cholesterol ester transfer protein (CETP) activity → reduces LDL production
HUMANS:
- Carry most cholesterol in LDL (“bad cholesterol”)
- Have CETP activity → LDL → atherosclerosis
183
what is the theorized mode of action for hypertryglicermia causing pancreatitis?
Triglycerides are hydrolyzed by pancreatic lipase, leading to excessive FFA production, which is thought to be toxic to the pancreas
Chylomicrons → plasma hyperviscosity → capillary plugging → ischemia
Increased risk of pancreatitis with severe HTG (triglycerides >500-800 mg/dL)
184
what are the sequela of hyperlipidemia on the hepatobilliary system?
Vacuolar hepatopathy
- Hepatocellular accumulation of triglycerides +/- glycogen
- ALP elevations occur with HTG & correlate with severity
Gallbladder mucocele
- Associated with HTG and hypercholesterolemia
- Hypersecretion of mucinous bile, decreased bile flow and GB motility, cystic, hepatic, CBD obstruction
185
what oclular changes do you see with hyperlipidemia?
intraocular xanthogranuloma in mini schnauzers
186
why do hyperlipidemic patients develope diabetes?
Insulin resistance has been possibly associated with hypertrygliceremia (esp in mini schnauzers)
Serum insulin decreases with treatment of HTG (ultralow fat diet; although the reason is unclear) -> IR likely improved with decreased serum lipid concentration
Theory of MOA
- Abnormal hepatic diacylglycerol (TG intermediate) and ceramids → decreased adipose insulin responsiveness
- LPL haplotypes may be associated with hepatic IR
- HTG associated with inflammation and increased TNFa
187
when is it recomended to treat hyperlipidemia?
fasting triglyceride >200 mg/dL or cholesterol >500 mg/dL
188
How should a hyperlipidemic patient be treated?
Low fat diet is indicated in both primary (life long) and secondary (until underlying managed) hyperlipidemia → decreased lipid absorption
- <2-2.5 g/100 Kcal is considered low fat
- Recheck serum lipids 3-4 weeks after starting diet
Fibrates (fenofibrate bezefibrate)
- Peroxisome activated receptor agonist -> activate LPL -> decrease triglyceride sunthesis (via Diacylglycerole acetyltransferase 2 inhibtiion), stimulaes hepaty fatty acid uptake
Statins (atorvastatin)
- Reversible HMG-CoA reductase inhibitor (rate limiting step for cholesterol synthesis; inhibition increases hepatic LDL uptake)
Omega-3 Fatty Acids
- Reduced lipogenesis, increased B-oxidation, increased LPL activity
189
what are fibrates? how do they work and side effects
ibrates (fenofibrate bezefibrate)
- Peroxisome activated receptor agonist -> activate LPL -> decrease triglyceride sunthesis (via Diacylglycerole acetyltransferase 2 inhibtiion), stimulaes hepaty fatty acid uptake
Occasional diarrhea and flatulence
Myopathy if used with a statin
Hepatotoxicity reported in humans
190
what are statins ? how do they work? side effects ?example of drug?
Reversible HMG-CoA reductase inhibitor (rate limiting step for cholesterol synthesis; inhibition increases hepatic LDL uptake)
Polyphagia, procoagulant state, and possible hepatotoxicity Myopathy if used with fibrate
Atorvastatin
