Lipid metabolism Flashcards
How much energy does 1g of fat provide?
9kcal (39kJ)
How much energy is stored as triacylglycerols in a lean individual?
3000,000 kJ
Why is fat vital?
Adipose tissue protects vital organs, insulates us from cold and gives our bodies & faces their shape
How much fat can we store?
Unlike glycogen, where the amount is limited, we can theoretically store an infinite amount of fat – and in evolutionary terms , it will have been in our best interest to be efficient storers of energy
What are the main roles of lipids?
-Constituents of membranes (Cholesterol, phospholipids, sphingolipids and glycolipids)
-Sources of metabolic energy
(Triacylglycerols (storage), fatty acids
and ketone bodies)
-Hormones
(Steroids and eicosanoids)
-Other
(Bile salts and waxes)
What are the two types of fats?
Saturated or unsaturated
What are essential fatty acids
They are fats that we cannot make in the body and are usually PUFAs – that are precursors for important signalling molecules – prostaglandins, thromboxanes
What is the main function of a triacylglycerol?
Main storage from of lipids in humans
What is the main function of a phospholipidsl?
Major component of cell membranes
Examples include:
phosphatidyl cholines
phosphatidyl inositols
How are triaclglycerols synthesised?
Fatty acids activated by attachment to Coenzyme A (CoA)
Fatty acids are added to glycerol-3-P by glycerol phosphate acyltransferase
Removal of phosphate group by a phosphatase before final fatty acid addition
Either synthesised from glycerol or from dihyroxyacetone
What are the enzymes responsible for lipolysis?
1 – desnutrin (ATGL) + hormone sensitive lipase (HSL)
2 – HSL
3 – HSL + monoacylglycerol lipase
What is the process of lipolysis?
Triacylglycerol –> Diacylglycerol –> Monoacylglycerol –> Glycerol
Where are Triacylglycerols stored?
Triacylglycerols stored in fat cells (adipose tissue) and in skeletal muscle
Where does Triacylglycerol synthesis and breakdown occur?
In the cytosol
When does lipolysis occur?
Starvation, cold and exercise
What hormone controls lipolysis?
hormone-sensitive lipase
What hormones increase lipolysis and which reduce?
INCREASE
Adrenalin, noradrenalin (via β-adrenergic receptors), glucagon & growth hormone
DECREASE
Adrenalin, noradrenalin (via α2-adrenergic receptors), & insulin reduce lipolysis
What is the difference in lipolysis control in the muscle?
in muscle, control of HSL is different – AMPK is the prime controlling mechanism
Go through the regulation of adipose triacylglycerol metabolism
GPCR1 = beta adrenergic receptor, GPCR2 = alpha 2 adrenergic receptor
Stimulatory and inhibitory G – protein coupled receptor (GPCRs) modulate cAMP levels. Insulin receptor binding decreases cAMP levels by increasing activity of phosphodiesterase.
Hormone bind to the receptors which activate g proteins which activate an enzyme that converts ATP to cyclic AMP. This causes another few steps until protein kinase A is activated and therefore hormone sensitive lipase.
What are perilipins?
They are in adipose tissue and also regulate lipolysis. Under basal conditions they prevent lipolysis but under stimulation by catecholamines perilipin allows lipolysis.
How do perilipins work?
ATGL (desnutrin) and HSL are physically prevented from binding to the lipid droplet by the perilipin which surrounds it. Once phosphorylated by PKA, the perilipin is no longer able to block access of desnutrin and activated HSL (note that phosphorylation activated HSL, but inactivates perilipin, allowing increased lipolysis
How is hormone sensitive lipase regulation different in muscle during exercise?
HSL is activated by protein kinase A via adrenalin binding to β-adrenergic receptors
Elevated calcium levels activate other protein kinases e.g. protein kinase C
Raised AMP levels also activate AMP-activated kinase (AMPK) – this is the main regulator of HSL phosphorylation in active muscle
How does training chnage activation of desnutin?
Training increases the activation of desnutrin in muscle
What are the problems with fats?
Triacylglycerols and fatty acids are very hydrophobic – INSOLUBLE in aqueous environments
They need to be transported round the body in association with proteins (LIPOPROTEINS/ALBUMIN)
Transporters are also needed to transport fatty acids effectively across cellular and organelle membranes in addition to diffusion (Fatty acid binding proteins and translocases)
What happens to fatty acid transporter proteins in muscle after endurance and high intensity training?
Endurance and high intensity interval training increase levels of fatty acid transporter proteins in muscle – enhancing efficiency of fatty acid utilisation during exercise
What is the function of Chylomicrons?
deliver triacylglycerols to the muscles and adipose tissue from the intestine via circulation system.
What is the function of VLDL?
form IDLs and LDLs as TAG is removed
What is the function of IDL?
transfer lipids to liver forming LDLs which are enriched in cholesterol.
What is the function of LDL?
deliver cholesterol from liver to other
cells. (“bad” cholesterol).
What is the function of HDL?
transport cholesterol from tissues to the liver. (opposite function to LDL). Lipid-depleted HDL then re-enters the circulation. (“good” cholesterol).
How do fatty acids arrive at peripheral tissue?
- in chylomicrons or VLDL released by lipoprotein lipase
- from adipose tissue fatty acids transported to tissues bound to albumin
how are fatty acids activated for oxidation for energy?
They are then activated by attachment to CoA and oxidised in a 4 step repeated pathway to produce acetyl CoA
Why can’t the brain oxidise fatty acids?
The fats cannot cross the blood brain barrier
What is the overall reaction to from acetyl coA from fatty acids?
fatty acid + ATP + CoA –> acyl-CoA + PPi + AMP
How is acetyl coA transported from the cytosol to the mitochondria?
by carnitine
What enzymes are used to create carnitine and so move aceltycoA across the blood brain barrier?
1- carnitine palmitoyl transferase I
2-Carnitine palmitoyltransferase II
What are the 4 steps of Fatty acid oxidation in the mitochondrion?
Fatty acyl-CoA –> acetyl CoA
- Oxidation by flavoenzyme acyl-CoA dehydrogenase (AD) –> C=C (trans)
- Hydration of C=C by enoyl-CoA hydratase (EH) –> 3-L-hydroxyacyl-CoA
- Oxidation by 3-L-hydroxyacyl-CoA (HAD) –> β-ketoacyl-CoA
- C-C cleavage by CoASH (catalyst β-ketoacyl-CoA thiolase (KT) –> fatty acyl-CoA (2C shorter) and acetyl CoA
What does fatty acid oxidation produce?
Fatty acid oxidation produces NADH & FADH2 which feed electrons into the electron transport chain for ATP synthesis, and acetyl CoA which feeds into the Krebs Cycle
How is fatty acid oxidation different to glycolysis?
Unlike glycolysis, no ATP formed directly – NO energy can be formed from fats in anaerobic conditions
What is the difference in overall ATP produced from fatty acids to glucose?
Overall reaction produces 108 ATP from each molecule of palmitoyl CoA (compare 30-32 from a molecule of glucose)
What is the difference in oxidation in unsaturated and saturated fatty acids?
Unsaturated fatty acids require additional steps to converts cis double bonds to trans form
How is the rate of fatty acid oxidation regulated?
Fatty acid oxidation in largely regulated by access of fatty acids to the mitochondria – this is controlled by the concentration of malonyl CoA
How does malonyl CoA inhibit fatty acid oxidation?
Malonyl CoA is formed by acetyl CoA carboxylase - first step of fatty acid synthesis
High [malonyl CoA] inhibits carnitine acyl-transferase-1
This ensures that fatty acid breakdown is inhibited when energy is plentiful
How are ketone bodies formed?
Ketone bodies are formed from excess acetyl CoA
When does ketone synthesis occur?
Synthesis occurs in the mitochondria of liver cells under conditions where the body relies on fatty acid oxidation for energy
fasting/v low CHO diets
uncontrolled diabetes
Ketone bodies are released into the blood and are oxidised to produce energy in peripheral tissues including brain tissue
What can high ketone body levels lead to?
ketoacidosis
Why do starving/fasting individuals synthesise ketones?
Low carbohydrate intake – insulin low, glucagon high
Glycolysis is inhibited, [pyruvate] low
Gluconeogenesis is NOT inhibited – oxaloacetate & malate being removed to form glucose
In the absence of insulin, fatty acids are mobilised from adipose tissue and oxidised to acetyl CoA – acetyl CoA levels HIGH
But lack of oxaloacetate prevents acetyl CoA from entering the Krebs cycle
So ketones are synthesised instead
Where does fatty acid synthesis occur?
- mainly in the liver in the cell cytoplasm
- in adipose tissue
- in breast tissue during lactation
As Acetyl CoA cannot cross the inner mitochondrial membrane what happens?
Acetyl CoA binds with oxaloacetete to form citrate which moves into the cytosol where acetylCoA is released and oxoacetete reformed.
NADH then binds too oxaloacetete to form malate, NADPH is then released and pyruvate is formed which then goes back to the mitochondria were it is converted to oxaloacetete and the cycle can continue
How many complex sites are there on the Fatty acid synthase complex (FAS)?
7
How many steps are there in fatty acid synthesis?
4
Two reduction steps and one dehydration step
What is the initial product of fatty acid synthesis?
Palmitate
What controls the rate of fatty acid synthesis?
Acetyl CoA carboxylase
What affects the activity of Acetyl CoA carboxylase?
Phosphorylation affects activity of Acetyl CoA carboxylase -
phosphorylation, glucagon and high [AMP] (low energy level) inactivates enzyme
activated by high [citrate] (signals high acetyl CoA) and insulin
Where is cholesterol mainly obtained?
From the diet – eggs (yolk), liver, meat – i.e. mainly animal sources
Intake from < 50 mg/day (vegetarians) to 750mg/day
Synthesis – in almost all tissues - mainly in the liver and intestine
How is cholesterol transported?
In LDL
Why do we need cholesterol?
membranes, Vitamin D, Hormones and bile salts
What are the 4 steps of cholesterol biosynthesis?
- Acetyl CoA to mevalonate (C6)
- Mevalonate to phosphorylated isoprene units (C5) (activation)
- Polymerise 6 isoprene units to form C30 chain (squalene)
- Cyclisation to form ring structure (lanosterol) then cholesterol
Where does cholesterol biosynthesis occur?
Occurs in cytosol and smooth endoplasmic reticulum
What is Familial hypercholesterolaemia?
lack of LDL receptors - sufferers are at increased risk of coronary disease
What does a high level of LDL increase risk of?
atherosclerosis
What does HDL do?
HDL involved in reverse cholesterol transport returning cholesterol from peripheral cells to liver
What is tangier disease?
lack of HDL – sufferers are at increased risk of coronary disease
What is an atherosclerosis?
Atherosclerosis is caused by the build-up of lipids in the walls of blood vessels (coronary artery).
This damages the vessel wall and a plaque forms of cholesterol, cholesterol esters and macrophages, surrounded by muscle cells that may undergo calcification
If the plaque ruptures,
a blood clot can form blocking
the vessel and causing
a heart attack or stroke
