Lipid metabolism and pathways Flashcards
Lipid function
- Essential components of cell membranes e.g. phospholipids, glycolipids, cholesterol
- Energy generation and storage i.e. triglycerides
- Inter- and Intra-cellular signalling events e.g. precursor of steroid hormones
- Metabolism e.g. bile acids
TG
Major form of metabolic energy storage in humans
Hydrophobic in nature
Metabolic pathways
Series of connected enzymatic reactions that produce specific products
Metabolite = reactants, intermediates and products
Metabolite
reactants, intermediates and products
TG - digestion and absorption
TG emulsified by bile acids
TGs are hydrolysed by enzyme Pancreatic Triacylglycerol lipase
Pancreatic triacylglycerol lipase
Hydrolyse Gs
TG metabolism
Oxidation in mitochondria to release energy in ATP form
Synthesis of TG from acetyl-CoA
Oxidation of TGs
Oxidation of long chain fatty acids to 2C fragments (acetyl-CoA)
Oxidation of acetyl-CoA to CO2 in citric acid cycle
Transfer electrons from reduced electron carriers to mitochondrial respiratory chain
B-oxidation
Process releases free energy - successive removal of 2C fragments from fatty acids
Mitochondria and peroxisomes
Fatty acids activated by attachment to CoA (Cytosol)
Transfer Acyl-CoA across mitochondrial membrane (rate limiting)
Progressive oxidation of FA by removal of 2C units to form A-CoA
Each cycle (shorten by 2C) produces:
A-CoA
FADH2
NADH
Fatty acid synthesis
Occurs mostly in liver and adipocytes
Longer chain carbon molecules built from 2C
Occurs in cytosol (A-CoA in mitochondrial)
FA biosynthesis
Citrate -> Acetyl CoA -> Malonyl CoA
Both A-CoA and M-CoA bind to FA synthase
Condensation reaction adds to 2C - involves M-CoA
Rate limiting steps
B-oxidation
FA synthesis
B-oxidation: transfer A-CoA into mitochondria
FA synthesis: Form M-CoA from A-CoA (acetyl CoA carboxylase)
Activation of A-CoA carboxylase
Insulin favours dephosphorylation of A-CoA carboxylase
Complex control of gene expression of lipogenic enzymes
Excess dietary intake of some polyunsaturated fatty acids can repress the synthesis of these enzymes in the liver
Cholesterol
Amphipathic
Synthesised by A-CoA and eliminated as bile acids
Storage = cholesterol esters
Cholesterol role
Important lipid membrane component
Precursor of steroid hormones
Source of bile acids
Bile acids role
Lipid digestion
Lipid absorption
Cholesterol excretion
Statins
Competitive inhibitor of HMG-CoA reductase
Bulky - prevent binding with substrate
Lovastatin (Mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor).
Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol)
Lovastatin
Natural
Mevacor
Mevacor
Lovastatin
Natural
Compactin
Natural
Pravastatin
Pravachol
Natural
Pravachol
Pravastatin
Natural
Simvastatin
Zocor
Natural
Zocor
Simvastatin
Natural
Atorvastatin
Lipitor
Synthetic
Fluvastatin
Lescol
Synthetic
Transport of lipids around body
Dietary lipids to cells - 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 tissue to liver for excretion
Transport lipids in blood
Short Chain FA transported bounded to blood proteins
Bulk transport (neutral lipids) insoluble in water, require special carrier proteins (lipoprotein)
Lipoproteins are composed of hydrophilic, hydrophobic and amphipathic molecules
Lipid transport
- Chylomicrons: deliver dietary TGs to muscle and adipose tissue + 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
Tangier disease
Cells laden with cholesterol and few HDL are formed bc of mutation in ABCA1 enzyme - allows cholesterol efflux from cells
ABCA1 enzyme
Allows cholesterol efflux from cells
Lipid uptake in cells
- Chylomicrons and VLDL particles give up lipid (TG) to tissues by the action of tissue-bound lipases
- The liver recognises remnants of these particles by their ApoE content, and takes them up for re-cycling
- LDL particles contain ApoB-100, which is recognised by cell surface LDL receptors
ApoB-100
Recognised by cell surface LDL receptors
Further regulation of cholesterol uptake - control LDL receptors
PCSK9 binds to LDL receptor and results in its degradation
PCSK9: Less LDL receptor on cell membranes and higher plasma LDL-C
PCSK9
Less LDL receptor on cell membranes and higher plasma LDL-C
proprotein convertase subtilisin/kexin type 9
Antibodies for PCSK9
Evolocumab (Repatha) and alirocumab (Praluent) are monoclonal antibodies that bind to PCSK9 - produce profound reduction in circulating LDL cholesterol
