TBL 7 Lipid Metabolism Flashcards
B-oxidation of fatty acids occur in the _________ of the cell, and gives rise to form ______.
mitochondria; acetyl-CoA
(Saturated/unsaturated) fatty acids have a higher melting point. They are thus solids at room temperature.
Saturated
Fats are stored in the cytoplasm as _________ compounds.
triacylglycerol (TAG)
Fats are stored in ____ cells.
adipose (fat cells)
Bile salts are generated from ______ in the _____ and stored in the _______.
generated from cholesterol in the liver, stored in gallbladder
Bile salts _____ bulky fat globules in the intestine.
emulsifies
_______, also known as fatty stool, is a symptom due to the lack of bile salts which causes indigestion and malabsorption of fats into the blood, causing most of the fat to pass through the gut undigested.
Steatorrhoea
Bile salts have a hydrophobic and hydrophilic face and form ______ in aqueous environment to shield hydrophobic TAGs form the solution.
micelles
Bile salts increase the surface area of TAGs for ______ to bind and digest TAGs.
pancreatic lipase
Once the TAGs are incorporated into chylomicrons, these lipoproteins enter the ______ and are transported by the _____ and returned to the blood.
enter the lacteal and are transported by lymph
Orlistat inhibits _____, reducing fat absorption in the intestines and undigested fat is excreted through faeces.
gastric and pancreatic lipase
1st step of B-oxidation:
Fatty acid —> ________ by enzyme _______. This step utilises 2 high energy bonds of ATP, and occurs on the ____________.
Fatty acid is converted to acyl-CoA, by acyl-CoA synthetase.
Occurs on the outer mitochondrial membrane
2nd step of B-oxidation:
Acyl-CoA produced has to be transported from the outer mitochondrial membrane into the ____. This is done via the _______ shuttle.
Acyl-CoA has to be transported into the mitochondrial matrix. This is done via the carnitine shuttle.
How the carnitine shuttle works:
Acyl-CoA will be coupled with carnitine to form ________ by enzyme _____, and is moved to the matrix by a ______.
Acyl-carnitine is then converted back to carnitine by ____, transferring the acyl group to CoA to reform _______.
How the carnitine shuttle works:
Acyl-CoA will be coupled with carnitine to form Acyl-carnitine by enzyme CAT I, and is moved to the matrix by a translocase.
Acyl-carnitine is then converted back to carnitine by CAT II, transferring the acyl group to CoA to reform acyl-CoA.
3rd step of B-oxidation:
A) Acyl-CoA will first be ______ by enzyme _________.
Cofactor ____ is reduced in the process, forming ____.
A) Acyl-CoA will first be oxidised by enzyme acyl-CoA dehyodrogenase.
(H atoms are removed from alpha and beta C, forming C=C bond).
Cofactor FAD to FADH2.
3rd step of B-oxidation:
B) Intermediate then undergoes hydration by enzyme ________.
enzyme 3-hydroxyacyl CoA hydrolase
OH group added to beta C, H atom added to alpha C
3rd step of B-oxidation:
C) Intermediate then undergoes ________ by enzyme ________.
Cofactor ___ is reduced in the process, forming NADH.
Intermediate undergoes oxidation by enzyme 3-hydroxyacyl CoA dehydrogenase.
(removal of H atom at Beta C to form C=O group)
Cofactor NAD+
3rd step of B-oxidation:
D) Intermediate then undergoes ______ by enzyme __________, forming one molecule of acetyl-CoA and a shortened molecule of acyl-CoA.
The cycle repeats until the last cycle where 2 acetyl-CoA molecules are produced.
Intermediate then undergoes thiolysis by enzyme thiolase.
Palmitic acid (fatty acid) consists of ___C. It is used to produce pamitoyl-CoA, which undergoes __ cycles of B-oxidation to produce __ molecules of acetyl-CoA.
16 Carbons atoms
7 cycles of B-oxidation; 8 molecules of acetyl-CoA
For odd-numbered fatty acids, the last cycle of B-oxidation will result in the production of a 3C propionyl-CoA, which will be converted to ________ which can enter the Krebs’ cycle.
Succinyl-CoA (4C)
In the first step of B-oxidation where acyl-CoA is oxidised using enzyme acyl-CoA dehydrogenase, there are 5 different types of enzymes specific to the _____ of fatty acid chains.
length
Fact: Primary carnitine defiency is due to a loss-of-function mutation to the gene which encodes a carnitine transporter. This causes reduced ability to take up carnitine required for B-oxidation.
No answer needed :)
______ is the proccess of producing fatty acids from acetyl-CoA and malonyl-CoA via sequential decarboxylative condensation reactions.
Lipogenesis
The enzymes involved in lipogenesis are:
1)
2)
1) Acetyl-CoA carboxylase
2) Fatty acid synthase (FAS)
Fatty acid synthase (FAS) consists of 9 different domains and 7 different enzymes. These 7 different enzymes are:
A and B are involved in transferring ACP group onto acetyl-CoA and malonyl-CoA.
C is involved in the next step of condensation between acetyl-ACP and malonyl-ACP to form B-ketoacyl ACP.
D is involved in the following step of reduction to form 3-hydroxyacyl ACP.
E is involved in the following step of dehydration.
F is involved in the last step of reduction, to form a R group.
A and B: Acetyl-ACP transferase; Malonyl-ACP transferase;
C: B-ketoacyl synthase;
D: B-ketoacyl reductase;
E: 3-hydroxyacyl-ACP dehydrases 1 and 2 (dehydration);
F: Enol-ACP reductase
Desaturation of fatty acids (to form unsaturated fatty acids) involve the enzyme ___________.
Fatty acyl-CoA desaturases
Dietary cholesterol uptake in humans is limited to approximately ___g/day.
0.5
Cholesterol biosynthesis takes place in the (organ).
liver
Cholesterol biosynthesis takes place in three main steps:
1) Generation of ________ (a reduced 3x acetyl-CoA molecules)
2) Activation of melovanate to ________ (C5 precursor isoprene unit) which is then elongated to form ______ (C30).
3) Cyclisation and ________ of squalene to form cholesterol. (C27)
1) Generation of mevalonate (C6)
2) Activation of mevalonate to isopentenyl-PP (C5) which is then elongated to form squalene. (C30)
3) Cyclisation and demethylation of squalene to form cholesterol
In mevalonate synthesis, __ acetyl-CoA molecules come together to form ________, which is then reduced by _________ to form mevalonate.
3 acetyl-CoA molecules come together to form HMG-CoA (6C), which is then reduced by HMG-CoA reductase to form mevalonate.
Statins competitively binds to _______, and thus they are used to block the synthesis of mevalonate from acetyl-CoA, inhibiting cholesterol synthesis.
HMG-CoA reductase
HMG-CoA is under ______ feedback control by bile salts, cholesterol and mevalonate.
negative
Mevalonate (C6) then undergoes sequential ________ at the hydroxyl groups at positions 3 and 5 to form _________ (C6). This is then decarboxylated to form isopentenyl-PP (C5), which is isomerised to form ____________ (C5).
Mevalonate (C6) —> Mevalonate-3-phospho-5-pyrophosphate (C6) —> Isopentenyl-PP (C5) —-> 3,3-dimethyl PP (C5)
3,3-dimethyl PP (C5) then undergoes condensation with another unit of _________ to form _________ (C10).
Third isopentenyl-PP is added to form the intermediate __________ (C15), two of which condense to form squalene (C30) and two pyrophosphates.
3,3-dimethyl PP (C5) + Isopentenyl-PP (C5) —-> Geranyl PP (C10)
Geranyl-PP (C10) + Isopentenyl-PP (C5) —-> Farnesyl-PP (C15)
2x Farnesyl-PP (C15) —> Squalene (C30)
Condensation of 2 x Farnesyl-PP to squalene is driven by the reducing power of ______.
NADPH (cholesterol biosynthesis)
Squalene (C30) is cyclised to cholesterol by first being reduced by ___ and _____ to form squalene-2,3-epoxide.
O2 and NADPH
The enzyme _____________ catalyses the formation of lanosterol from squalene-2,3-epoxide.
Squalene epoxide lanosterol-cyclase
Lanosterol is then reduced, with the removal of ________ to form cholesterol.
3 methyl groups
The steroid precursor _________ is derived from cholesterol via the action of the enzyme _______.
Steroid precursor pregnenolene is derived from cholesterol via the action of desmolase.
__________ biosynthesis from cholesterol involves UV radiation, as it is required to initiate the reaction in epidermal keratinocytes.
Vitamin D
______ is formed from Vitamin D3 and it plays a key role in calcium metabolism.
Therefore, vitamin D deficiency can cause _____ (in children) or osteomalacia in adults, leading to softened or weakened bones.
Calcitriol; cause Rickets in children
Bile salts are derived from ______.
cholesterol
Primary bile salts include ______ and ______.
glycocholate and taurocholate
_________ are fluctuating assemblies of cholesterol and sphingomyelins in the plasma membrane, which helps to organise cell signalling by localising key proteins.
Lipid rafts
Cholesterol is attached to the N-terminus of ________- proteins during its processing, limiting diffusion within tissues, which is essential for successful limb formation during embryogenesis.
Hedgehog-signalling protein
_______ are composed of a phospholipid monolayer containing (un-/esterified) cholesterol and apoproteins.
Lipoproteins; unsterified cholesterol
HDL transports cholesterol from the ________ to the ______. It is therefore known as the ‘good’ cholesterol, as it picks up excess cholesterol in the blood stream and lowers the total serum levels.
from peripheries to the liver
LDL transport cholesterol from the ______ to the _______. It is therefore known as the ‘bad’ cholesterol, as it has the potential to clog up the arteries.
from the liver to the peripheries
__________ is an enzyme found on capillary endothelial cells lining various tissues. It catalyses the hydrolysis of triacylglyceries (TAGs) to glycerol and fatty acids.
Lipoprotein lipase
Familial hypercholesterolemia (FH) is a monogenic (dominant/recessive) trait in the LDL receptor gene.
dominant
FH may cause superficial ________ in the body, arising from plasma LDL-derived cholesterol deposits in skin macrophages.
xanthomas
Cholesterol in the form of LDL is taken up into cells via __________ by cell surface receptors.
receptor-mediated endocytosis
The LDL receptor has five domains:
- Cytoplasmic domain
- O-linked carbohydrate
- Ligand-binding
- EGFP (pH dependent)
- Transmembrane (holds the recceptor in the plasma membrane)
The _______ domain of the LDL receptor localises the receptors to clarithin-coated pits and triggers receptor-mediated endocytosis.
cytoplasmic
Class __ LDLR mutation occurs when there is no synthesis of the LDLR. This might be caused by a ______ mutation, causing a non-functional protein.
Class I LDLR mutation
Might be caused by a deletion/frameshift mutation/mutation in the promoter region
Class ___ LDLR mutation occurs when there is ineffective ligand binding. This might be caused by a mutation in the _____ region of the gene, which is the ligand-binding region.
Class III LDLR (ligand-binding)
N-terminus region
Class IV LDLR mutation occurs when the _________ of the receptor is affected. There is therefore no clustering of the clathrin-coated pits.
cytoplasmic domain
Class V LDLR mutation occurs when there is a mutation in the ____ domain. Endocytosis occurs, but there is no recycling of the LDLR to the surface as LDL is not released from the LDLR.
EGFP domain (sensitive to pH changes causing conformational shift)
Class __ LDLR mutation occurs when there is a mutation throughout the coding region, which leads to LDLR not being properly transported to the GA and therefore low surface expression.
II
Resins/sequesterants (cholestyramines) bind and sequester _________ to prevent intestinal absorption.
bile acid-cholesterol complexes
Muscles (40% of body weight) can metabolise _______ and ______.
carbohydrates and fats (B-oxidation)
Brain and nervous tissue (2% of body weight) can metabolise _____ and ______. It cannot metabolise _____.
Can metabolise carbohydrates (glucose) and ketone bodies; cannot metabolise fats
Adipose tissue (15% of body weight) can metabolise ________ and ________.
carbohydrates and fats (B-oxidation)
The heart (1% body weight) can metabolise ____ and ______.
It accounts for ___% of the BMR as it needs to beat continuously. It is completely (aerobic/anaerobic).
can metabolise carbohydrates and fats.
10% of BMR, completely aerobic.
The liver (2.5% of body weight) metabolise _____ and ____. It accounts for __% of the B,R and is the main glycogen store.
carbohydrates and fats; 20% of BMR
The (organ) fuels the body during activation. It is highly metabolically active and can inter-convert nutrient types. It is also involved in lipoprotein metabolism.
liver
During glycolysis, excess glucose-6-phosphate is converted to ______ and stored in the _____ and _____.
Excess glucose-6-phosphate is converted to glycogen and stored in the liver and skeletal muscles.
During link reaction, excess acetyl-CoA can be converted into _____ and _______.
fatty acids and cholesterol (lipogenesis)
During Krebs cycle, pyruvate and other intermediates can be metabolised to produce _________.
amino acids
___________ is the process of making glucose or glycogen from oxaloacetate. It only occurs in the (organ).
Gluconeogenesis; only occurs in the liver
Gluconeogenesis requires the hydrolysis of ATP to provide energy. There is a net loss of ___ ATP.
Net loss of 6 ATP
1st step of gluconeogenesis:
Enzyme ___________ is activated allosterically by _____, and carboxylates pyruvate (3C) to form ______.
Enzyme pyruvate carboxylase is allosterically activated by acetyl-CoA, and carboxylates pyruvate (3C) to form oxaloacetate. (4C)
*Acetyl-CoA is accumulated because TCA cycle is halted. (Due to oxaloacetate being diverted to form glucose)
2nd step of gluconeogenesis:
Oxaloacetate (4C) will be converted to _______ (3C) by enzyme ___________.
oxaloacetate (4C) –> phosphoenolpyruvate (3C)
by enzyme phosphoenolpyruvate carboxykinase
3rd step of gluconeogenesis:
Phosphoenolpyruvate (3C) —-»» __________ (reverse glycolysis)
fructose-1,6-bisphophate (6C)
4th step of gluconeogenesis:
Enzyme ___________ catalyses the removal of a phosphate group from fructose-1,6-bisphosphate to form fructose-6-phosphate.
fructose-1,6-bisphosphatase
5th step of gluconeogenesis:
Enzyme _______ then removes the last phosphate group from glucose-6-phosphate to form glucose.
G-6-phosphatase
Fats can feed into the Krebs’ cycle by being broken down into _______, which can be converted to _______.
Fats —> Acetyl-CoA (B-oxidation) —> Ketone bodies (which can be used by the heart tissue)
Under anaerobic conditions, ATP demand cannot be matched by oxygen delivery and glucose transport. Myocytes will utilise their own ______ and _____ stores.
glycogen and fatty acid stores
The control of glucose metabolism usually occur in:
- steps that involve ________
- _____ steps
- _______ steps
- steps that involve enzymatic activity
- early steps
- irreversible steps
Glucose metabolism can be controlled by:
- ______
- ______
- Feedback loops
2. Signalling hormones
Blood glucose concentration is always maintained around ____.
4mM
Increased blood glucose concentration leads to increased blood transport into _____ and _____ cells.
liver and muscle cells
Muscle hexokinase I have a (low/high) glucose affinity, leading to very rapid conversion of glucose at low glucose concentrations.
Muscle hexokinase I - high glucose affinity
It is therefore highly sensitive to G6P-inhibition.
Liver hexokinase IV have a (low/high) glucose affinity, so it needs to have a certain accumulation of glucose in liver cells before maximal rate can be achieved.
Liver hexokinase IV - low glucose affinity
It is therefore less sensitive to G6P-inhibition.
When there is increased blood glucose concentration, there is increased glucose transport into liver and muscle cells. This glucose will then be converted to ________ by enzyme _______.
glucose-6-phosphate by enzyme hexokinases
Hexokinase is inhibited by the accumulation of the product _________. This is negative feedback.
G6P
There are two main types of hormonal control for blood glucose: ?
- Pancreatic hormones (Insulin, glucagon)
2. Adrenal hormones (Adrenaline, glucocorticoids)
Insulin is secreted by the __ cells in the islets of Langerhans in the pancreas.
B-cells
Type __ diabetes is the autoimmune destruction of B-cells that produce insulin. Patients therefore cannot make insulin.
Type I
Type __ diabetes refers to liver and muscle cells having reduced responsiveness to insulin.
Type II
In diabetes, tissues do not detect the glucose in the bloodstream.
Muscles must therefore break down _____ to produce amino acids as a means of generating energy via gluconeogenesis.
Excess glucose is generated by the liver to meet the needs of the various tissues, but is not taken up.
______ tissues begin to break down fat molecules - the increase in TAG catabolism results in higher ______ in the blood stream, which might undergo B-oxidation in the liver to produce increased concentration of _______.
Muscles break down proteins to produce amino acids.
Adipose tissues break down fat molecules to produce fatty acids.
Fatty acids will undergo B-oxidation in the liver to produce ketone bodies.
The pancreas is a highly _______ structure. This allows it to sense change in glucose concentration very acutely.
vascularised
Glucose enters the cell via ____ transporter on the plasma membrane.
GLUT-2
After a meal:
Increased glucose concentration leads to increased expression of the _____ gene in the cell.
insulin
After a meal:
Increased ATP closes the ____ channel, depolarising the cell membrane. This causes the opening of voltage-gated ___ channel, allowing the influx of ___ ions.
This would cause insulin-containing vesicles to migrate to the plasma membrane and fuse with it, releasing insulin into the bloodstream via _______.
Increased ATP (from glucose metabolism) closes the K+-ATP channel, depolarising the cell membrane. This causes the opening of voltage-gated Ca2+ channel, allowing the influx of Ca2+ ions. This would cause insulin-containing vesicles to migrate to the plasma membrane and fuse with it, releasing insulin into the bloodstream via exocytosis.
The release of insulin into the bloodstream leads to the activation of cell signalling cascades in the cell, one of which increases _____, leading to a change in the gene expression of the insulin gene. This is _______ feedback.
PI3’-kinase
Positive feedback loop
The bihormonal hypothesis of diabetes suggest that:
Insulin deficiency and relative excess of glucagon causes increased hepatic glucose output.
Insulin is able to act on pancreatic alpha cells such that the presence of insulin inhibits ______.
glucagon release
When the blood glucose starts to fall, ________ stimulates skeletal muscle cells to operate glycogenolysis and glycolysis, and adipose tissue towards lipolysis to generate fatty acids and glycerol, which are alternative substrates to glucose.
Adrenaline
