Lipid Metabolism Flashcards
What is the fatty acid synthesis pathway?
Involves a series of enzymatic reactions that ultimately lead to the production of fatty acids
What are some basic functions of lipids in cells?
Lipids play a wide range of functions in cells, including:
- energy storage
- structural roles
-insulation (electrical & thermal)
- surfactant
- signalling molecules
What are some examples of lipids as signalling molecules?
- hormones (e.g. steroids, leukotrienes)
- intracellular messengers (e.g. DAG)
What is the simplest form of a lipid?
- a fatty acid
- general structure = R-COOH, where R is a hydrocarbon chain of 5-36 carbons
What are some other forms of lipids?
- triacylglycerols as a storage form (also known as “fat”)
- phospholipids in cell membranes
- sphingolipids in the brain
How are fatty acids built up?
From successive additions of 2C units, which are derived from acetyl-CoA
Where are fatty acids synthesized?
Fatty acids are synthesized in the cytoplasm
How do acetyl-CoA molecules get from the mitochondria to the cytoplasm for fatty acid synthesis?
- acetyl-CoA → citrate in mitochondria
- then transported to the cytoplasm
- where it is converted back to acetyl-CoA & used for fatty acid synthesis
What is the actual molecule used to add 2C units in fatty acid synthesis?
malonyl-CoA
What is the main regulated step in fatty acid synthesis?
Acetyl CoA carboxylase is the main regulated step in fatty acid synthesis
What is the function of acetyl CoA carboxylase in fatty acid synthesis?
An enzyme that converts acetyl-CoA → malonyl-CoA
What is the equation of the conversion of acetyl-CoA to malonyl-CoA?
acetyl-CoA + ATP + HCO3- → malonyl-CoA + ADP + Pi + H+
What is the substrate in the first step of fatty acid synthesis?
malonyl ACP
What type of reactions occur after the first step of fatty acid synthesis (in order)?
- condensation
- reduction
- dehydration
- reduction
What is the 2nd condensation reaction/step of fatty acid synthesis?
butyryl ACP + malonyl ACP → acetoacetyl ACP
What is the enzyme involved in the 2nd condensation reaction of fatty acid synthesis?
acyl-malonyl-ACP (condensing enzyme)
What is the reduction reaction/step of fatty acid synthesis?
acetoacetyl ACP → D-3-hydroxybutyryl ACP
What is the dehydration reaction step of fatty acid synthesis?
D-3-hydroxybutyryl ACP → crotonyl ACP
What is the 2nd reduction reaction of fatty acid synthesis?
crotonyl ACP → butyryl ACP
What are the energy requirements for FA synthesis?
- Acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 20 H+ → Palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6H2O
- 7 Acetyl-CoA + 7 CO2 + 7 ATP → 7 Malonyl-CoA + 7 ADP + 7 Pi + 14 H+
- Overall equation:
8 Acetyl-CoA + 7 ATP + 14 NADPH + 6 H+ → Palmitate + 14 NADP+ + 8 CoA + 6H2O + 7 ADP + 7 Pi
What is the length and saturation level of the fatty acid produced by fatty acid synthase?
C16, and it is fully saturated
What is the general length of most fatty acids?
Most fatty acids are longer than C16, with C20, C22, and C24 being the most common lengths
Where does the elongation of fatty acids occur?
elongated in the smooth endoplasmic reticulum (ER)
What carbon is the most common site of desaturation in fatty acids?
C9
Can mammals desaturate fatty acids beyond C9?
No
Are there essential fatty acids that must be obtained from the diet?
Yes, there are essential fatty acids that mammals cannot synthesize and must be obtained from the diet
What is the storage form of fatty acids in the body?
triacylglycerols
What is the advantage of using triacylglycerols for energy storage?
They are a high-density form of energy storage
Where are triacylglycerols made in the body?
Triacylglycerols are made in the liver
How are triacylglycerols transported around the body in circulation?
Triacylglycerols are transported around the body in circulation with proteins as lipoproteins
Where are triacylglycerols stored in the body?
Stored in adipocytes to form white fat
What are the different types of lipoproteins?
- chylomicrons
- VLDLs, IDLs, LDLs, and HDLs
What is the function of chylomicrons?
Chylomicrons are the largest (>400kDa) lipoproteins
function: transport dietary TAGs & cholesterol from the intestine to muscle/adipose
Where are VLDLs, IDLs, and LDLs synthesised?
Synthesized in the liver
What is the function of VLDLs, IDLs, and LDLs?
To transport lipids to muscle/adipose
What is the function of HDLs?
to transport lipids/cholesterol to the liver, where excess cholesterol is excreted in bile
Where are HDLs synthesized?
HDLs are made in plasma
Why are LDLs considered ‘bad’ and HDLs considered ‘good’?
- LDLs are considered ‘bad’ as they can contribute to the development of atherosclerosis
- HDLs are considered ‘good’ as they scavenge lipids & have a protective effect against atherosclerosis
What is the starting molecule for the formation of triacylglycerols?
dihydroxyacetone phosphate (DHAP)
- a glycolysis intermediate
How is DHAP converted to glycerol-3-phosphate during triacylglycerol formation?
By generating NADH
What is the first intermediate formed during triacylglycerol formation?
- 2 FA chains are added to glycerol-3-phosphate
- to give phosphatidic acid
- which is the first intermediate formed during triacylglycerol formation
How is diacylglycerol formed during triacylglycerol formation?
- the phosphate group is removed from phosphatidic acid
- to give diacylglycerol during triacylglycerol formation
What is the final step in the formation of triacylglycerols?
The addition of a final FA chain to diacylglycerol
What are the advantages of fat storage over glycogen storage?
- fat has a higher energy content compared to glycogen, about 2.5-fold on complete oxidation
- unlike glycogen, fat is not hydrated, resulting in a total of ~4-fold more energy per gram dry weight
Are there any disadvantages to fat storage compared to glycogen storage?
- while fat stores are not limited, they can expand with food intake, which can lead to obesity & related health issues
- metabolism of fat is slower, making it better suited for longer-term storage rather than quick energy needs
How is triacylglycerol synthesis regulated by hormones?
insulin stimulates the synthesis of triacylglycerol
What are the different types of fat cell?
- white
- brown
What else can acetyl-CoA be turned into?
cholesterol and its derivatives, e.g. vitamin D, steroid hormones, bile acids
Can FAs generate signalling molecules?
Yes, FAs can generate signalling molecules
What are some examples of signalling molecules that can be generated from FAs?
arachidonic acid: component of membrane phospholipids that is released when broken down by phospholipase A2
further broken down to:
- PGG2 → PGH2 (prostaglandins)
- 5-HPETE → leucotrienes
(slide 16)
What are examples of PGH2 and its functions?
- prostacyclins
- prostaglandins
- thromboxanes
- inflammation, pain, gastroprotective PGs
What are some examples of Leucotriene A4 and its functions?
- leucotriene B4
- cysteinyl leucotrienes
- allergy, inflammation, gastric damage
How are TAG broken down?
- adrenaline & glucagon activate hormone sensitive lipase enzyme
- TAG → free FAs + glycerol
What is β-oxidation of FAs?
Metabolic pathway:
- that breaks down fatty acids into acetyl-CoA
- which can then enter the citric acid cycle & generate ATP
What is the importance of β-oxidation in metabolism?
- it is a major pathway for the breakdown of fatty acids
- this pathway allows the body to generate ATP from stored fat when glucose is not available
What is the reverse problem of FA synthesis in β-oxidation of FAs?
- fatty acids need to be transported into the mitochondrial matrix
- in order to be broken down through β-oxidation
Why is it necessary to transport FAs into the mitochondrial matrix for β-oxidation?
Because this is where the enzymes required for β-oxidation are located
Are all fatty acids fully saturated?
No, not all fatty acids are fully saturated
What happens during β-oxidation when an unsaturated fatty acid has a double bond between C3 and C4?
β-oxidation will continue as normal until the double bond is reached, at which point it will stop
What is the role of isomerase in the breakdown of unsaturated fatty acids?
Isomerase moves the double bond in an unsaturated fatty acid to a position between C2 and C3, allowing β-oxidation to continue
Will β-oxidation continue after the role of isomerase in the breakdown of unsaturated fatty acids?
Yes, β-oxidation will continue after isomerase moves the double bond in an unsaturated fatty acid to a position between C2 and C3
What happens during the breakdown of odd carbon fatty acid chains?
Successive rounds of β-oxidation will continue as normal until the final round
What are the final products of the breakdown of odd carbon fatty acid chains?
acetyl-CoA and propionyl-CoA (C3)
What happens to propionyl-CoA in the breakdown of odd carbon fatty acid chains?
Propionyl-CoA → succinyl-CoA
What is methylmalonic acidosis?
A condition where the body is unable to breakdown propionyl-CoA → succinyl-CoA
What is methylmalonic acidosis caused by?
Either:
- enzyme deficiency
- lack of coenzyme (deoxyadenosylcobalamin, a vitamin B12 derivative)
What are the symptoms of methylmalonic acidosis?
Includes neurological issues such as:
- seizures
- encephalopathy
- stroke
Is methylmalonic acidosis fatal if left untreated?
Yes, methylmalonic acidosis is fatal if left untreated
What are the treatments for methylmalonic acidosis?
Includes
- a low protein diet
- (in severe cases) liver or kidney transplant
Fates of acetyl-CoA from FA breakdown
- sterols (cholesterol) & FAs
- TCA cycle (aka citric acid cycle)
- ketone bodies
- protein acetylation (protein modification)
What molecules does the intrinsic regulation of fat metabolism include?
- citrate
- palmitoyl CoA
- malonyl CoA
What is the intrinsic regulation of fat metabolism?
- ↑ in citrate leads to an ↑ in fat synthesis
- while ↑ in palmitoyl CoA leads to ↓ in fat synthesis
- ↑ in malonyl CoA leads to ↓ in β-oxidation
What is the extrinsic regulation of fat metabolism?
Involves the effects of hormones such as insulin and glucagon
How does insulin regulate fat metabolism?
Insulin promotes fat synthesis and storage by:
- activating the enzymes involved in fat synthesis
- inhibiting those involved in fat breakdown
How does glucagon regulate fat metabolism?
Glucagon promotes fat breakdown & energy production by:
- activating the enzymes involved in β-oxidation
- inhibiting those involved in fat synthesis
Is all fatty acid breakdown carried out in the mitochondria?
No, not all fatty acid breakdown is carried out in the mitochondria - can also occur in peroxisomes
What is the role of peroxisomes in fatty acid breakdown?
Peroxisomes are involved in the breakdown of fatty acids and produce H2O2 as a byproduct
What is the role of H2O2 in peroxisomal fatty acid breakdown?
- H2O2 is produced during peroxisomal fatty acid breakdown
- is involved in oxidizing phenols and alcohols
Why is peroxisomal fatty acid breakdown important in liver function?
Because it plays a key role in liver detoxification processes
slides 22-26
What is medium chain acyl-CoA dehydrogenase (MCAD) deficiency?
Genetic disorder that affects fatty acid metabolism
- most common fatty acid oxidation disorder
- affecting approximately 1 in 20,000 newborns
What are the symptoms of MCAD deficiency?
- lethargy
- seizures
- coma
- hypoketotic hypoglycemia during fasting
Is there a screening test available for MCAD deficiency?
Yes, there is a neonatal screening test available for MCAD deficiency
What is long chain acyl-CoA dehydrogenase (LCAD) deficiency?
LCAD deficiency is a genetic disorder that affects fatty acid metabolism
- less common than MCAD deficiency
- affecting approximately 1 in 50,000 newborns
What are the range of symptoms of LCAD deficiency?
Range from benign to fatal
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What are the range of symptoms of VLCAD deficiency?
Range from benign to fatal
What is carnitine deficiency?
The inability to synthesize carnitine & transport across epithelia
- it has been linked to autism in males
What can carnitine deficiency lead to?
- muscle cramping
- severe weakness
- even death
What are the carnitine deficiences?
- carnitine acyltransferase
- carnitine/acylcaritine translocase
What does carnitine acyltransferase deficiency lead to?
- muscle weakness on exercise
- as short-chain fatty acids can enter the mitochondrial matrix unaided
What is atherosclerosis?
Atherosclerosis is a condition where:
- high levels of cholesterol (LDLs) can lead to the formation of plaques in the walls of arteries
- these plaques can break off or cause blood clots to form
How can atherosclerosis be treated?
Treated by
- restricting dietary cholesterol intake
- taking medications such as statins, which can help lower cholesterol levels in the blood
- other treatments may include lifestyle changes such as exercise & quitting smoking
What are the consequences of atherosclerosis?
Include:
- heart attacks
- strokes
- renal artery blockages
- other serious conditions
What is Zellweger syndrome?
Rare and serious genetic disorder that is linked to peroxisomes
- most severe form of the Zellweger syndrome spectrum
- failure to assemble functional peroxisomes
What are some of the symptoms of Zellweger syndrome?
- cause a range of abnormalities in the liver, kidney, muscle, CNS, and other organs
- associated with the accumulation of very long chain fatty acids (VLCFA) & branched chain fatty acids (BCFA), which are normally degraded in peroxisomes
How is Zellweger syndrome linked to peroxisomes?
- because it is caused by a failure to assemble functional peroxisomes
- which are organelles that play a key role in the metabolism of lipids & other molecules in the body
- the absence of functional peroxisomes leads to the accumulation of certain fatty acids that are normally degraded in these organelles
