Lipid metabolism Flashcards
Biological functions of lipids
Essential components of cell membranes
Energy generation and storage
Inter and intra-cellular signalling events
Metabolism
Triacylglyverols
Consider 90% of dietary lipids
Major form of metabolic energy storage in humans
Hydrophobic in nature
Metabolic pathways
Series of connected enzymatic reactions that produce specific products
Reactants, intermediates and products are known as ‘metabolites’
Triacylglycerols: digestion and absorption
TGs need to first be emulsified by bile acids
TGs then hydrolysed by pancreatic triacylglycerol lipase
Products of lipid digestion
Mixture of fatty acids and mono and diacylglycerols
Can be absorbed by intestinal mucosa
TG metabolism
2 major metabolic pathways:
- oxidation in the mitochondria to release energy in the form of ATP
- synthesis of TG from acetyl-CoA (for storage)
Oxidation of TGs
3 stages oxidation of fatty acids to CO2 and H2O:
- Oxidation of long chain fatty acids to 2-carbon fragments in the form of acetyl-CoA: beta oxidation
- Oxidation of acetyl-CoA to CO2 in the citric acid cycle
- Transfer of electrons from reduced electron carriers to mitochondrial respiratory chain
Beta oxidation
Successive removal of 2-carbon fragments from fatty acid
Occurs in mitochondria and peroxisomes
- fatty acids activated by attachment to CoA (cytosol)
- transfer of acyl-CoA across mitochondrial membrane (rate-limiting step)
- progressive oxidation of fatty acids by removal of 2-carbon units to form acetyl-CoA which enters the citric acid cycle
2 pools of CoA as it does not cross the inner membrane
Fatty acid synthesis
Occurs mainly in liver and adipocytes
Long carbon chain molecules built up from 2-carbon units derived from acetyl CoA
Occurs in the cytosol
Overview of fatty acid biosynthesis
Citrate-> acetyl coA -> malonyl CoA
Malonyl CoA and acetyl CoA both bind to fatty acid synthase
Series of condensation reactions involving amnolyl CoA adds further C2 units
Control of fatty acid oxidation and synthesis
Rate limiting steps:
- beta oxidation: transfer of acyl-CoA into mitochondria
- fatty acid synthesis: formation of malonyl CoA from acetyl-CoA, catalysed by acetyl CoA carboxylase
Cholesterol
Amphipathic lipid- OH
Synthesised from acetyl CoA and eliminated as bile acids
Storage form is cholesterol ester found in most tissues
Physiological roles of cholesterol
Important lipid component of biological membranes
Precursor of steroid hormones
Source of bile acids
Bile acids are polar derivatives of cholesterol and aid in
Lipid digestion
Lipid absorption
Cholesterol excretion
Cholesterol deposition in arteries
Associated with heart disease and stroke
Stage 1 of cholesterol biosynthesis
Acetyl CoA ->
HMG-CoA -> (NADPH- NADP+)(HMG-CoA reductase)
Mevalonate
Stage 2 of cholesterol synthesis
Mevalonate -> (3ATP-3ADP)( CO2)
Active isporenoids -> (NADPH- NADP+)
Squalene (C30)
Step 3 of cholesterol synthesis
Squalene (C30) -> (O2)(NADPH- NADP+) (squalene epoxidase/ cyclas)
Lanosterol (C30) (4-ring structure)
Stage 4 of cholesterol synthesis
Lanosterol (C30)-> (O2) (NADPH -NADP+) (3CH3)
Cholesterol (C27)
Cholesterol biosynthesis
Major sites: liver and intestine
Acetyl CoA -> HMG-CoA -> (HMG reductase) Mevalonate -> Squalene -> Cholesterol
Statins
Competitive inhibitors of HMG-CoA reductase
Prevents enzyme from binding with HMG-CoA
Two classes:
- natural statins
- synthetic statins
Natural statins
Lovastatin (mevacor)
Compactin
Pravastatin (pravachol)
Simvastatin (zocor)
Synthetic statins
Atorvastatin (lipitor)
Fluvastatin (lescol)
Transport of lipids around the body
Bring dietary lipids to cells for energy production or storage
Provide lipids from diet to cells for synthesising cell membranes
Move lipids from storage in adipose tissue for use in energy production
Carry cholesterol from peripheral tissues to liver for excretion
Transport of lipids in the blood
Short chain fatty acids transported bound to blood proteins like albumin
Bulk transport of neutral lipids, which are insoluble in water, requires special carrier proteins: lipoproteins
Lipoproteins
Composed of hydrophilic, hydrophobic and amphipathic molecules
Structure of lipoproteins
Outer layer of amphipathic phospholipids contains cholesterol and has apoliporoteins associated with it
Lipids carried in central core
Classes of lipoproteins
Chylomicrons (dietary TGL transport)
VLDL (endogenous TGL transport)
LDL (cholesterol transport)
HDL (reverse sterol transport)
Chylomicrons
Deliver dietary TGs to muscle and adipose tissue and dietary cholesterol to the liver
VLDL
Transport endogenous TGs and cholesterol
LDL
Transport cholesterol from liver to tissues
HDL
Transport cholesterol from tissues to liver i.e. remove cholesterol from tissues
Lipid uptake by cells
Chylomicrons and VLDL particles give up TG to tissues by the action of tissue bound lipases
Liver recognises remnants of these partiles by ApoE content, takes them up for recycling
LDL particles contain ApoB-100 which is recognised by cell surface LDL receptors
PCSK9
Binds to LDL receptor and results in its degradation
Effects of PCSK9
Less LDL receptor on cell membranes and higher plasma LDL-C
