Lipid metabolism and pathway Flashcards
Biological functions of lipids
Cell membranes- phospholipids, glycolipids and cholesterol.
Generation and storage- triglycerides.
Cell signaling events- precursor for steroid hormones.
Metabolism- bile acids
Triglycerides
90% of dietary lipids
Metabolic storage
Hydrophobic
Digestion of triacylglycerols
- Emulsification: broken down into smaller pieces by bile acids- increases SA for enzymic digestion
- Hydrolysis: Pancreatic triacylglycerol lipase.
- Absorption: products (fatty acids, mono/diacylglycerols), absorbed by intestinal mucosa.
Pancreatic triacylglycerol lipase
Enzyme that hydrolyses triacylglycerol into a mixture of fatty acids and mono/diacylglycerols
Which structure absorbs products of triglyceride digestion?
Intestinal mucosa
Summary of the oxidation of TGs
Location: mitochondria
Process:
TG—–> ATP, CO2 and H2O.
3 steps of oxidation
- Beta-oxidation:
Oxidation of fatty acid chain, 2 cardons at a time to form acetyl-CoA. - Citric acid cycle: Acetyl CoA is oxidised to CO2.
- Electron transfer from reduced electron carriers to mitochondrial respiratory chain.
Beta-oxidation
Location: mitochondria, peroxisomes.
Step 1: CoA attaches to fatty acids and activate it.
Rate determining step, Step 2: Transfer of acetyl-CoA across mitochondrial membrane
Step 3, progressive oxidation: 2 carbon units removed at a time to form acetyl-CoA-----> enters citric acid cycle. This step forms: 1 aceyl-CoA 1 FADH2 1 NADH
Transfer of fatty acids across the mitochondrial membrane
Carnitine shuttle transports long fatty acids- greater than 10 Cs.
There is a supply of CoA in both the cytosol and mitochondrial matrix- CoA not transported across inner mitochondrial membrane.
- Fatty acid is activated by acyl CoA via acyl CoA synthase—-> Fatty acyl-CoA
- Carnitine acyltransferase 1 causes CoA-SH to unbind and carnitine to bind to fatty acyl.
- Fatty acyl carnitine is transferred across membrane into mitochondrial matrix via carnitine carrier protein.
- Transferase II (matrix side of inner membrane), causes carnitine to unbind from fatty acyl carnitine and S-CoA to bind in the matrix.
- This allows fatty acyl-CoA to progress into beta oxidation
Fatty acid synthesis
Location: Cytosol of mainly hepatocytes and adipocytes, essentially in all cells.
Build up of long fatty acid chains 2 C a time- from acetyl CoA
Acetyl CoA source from mitochondria.
- Citrate is converted to acetyl CoA
- Carboxylation: Acetyl CoA converted to malonyl CoA- rate limiting step.
- Acetyl CoA and malonyl CoA both bind to fatty acid synthase to form fatty acids.
Transport of acetyl CoA out of the mitochondria
Citrate malate cycle:
- Acetyl CoA is converted into citrate via citrate synthase in mitochondrial matrix.
- Citrate exits the cell via tricarboxylate transporter. into cytosol.
- Citrate converted into oxaloacetate via citrate lyase.
Also produces Acetyl-CoA, when bound to CoA. - Maltate dehydrogenase converts OAA to malate.
- Malic enzyme converts malate to pyruvate.
Rate determining steps in fatty acid oxidation
Beta oxidation- transfer of acyl-CoA into mitocohondria.
Rate determining steps fatty acid synthesis
Carboxylation of malonyl CoA to form acyl CoA
Uses acyl CoA carboxylase
Control of fatty acid synthesis
Regulated by glucagon and insulin- controls phosphorylation
Insulin favours dephosphorylation which activates acyl CoA carboxylase
Roles of cholesterol
Component of biological membranes
Precursor for steroid hormones
Source of bile acids
Roles of bile acids
Lipid digestion
Lipid absorption
Cholesterol excretion
Summary of cholesterol biosynthesis
- Acteyl CoA converted to HMG-CoA.
- HMG-CoA converted to mevalonate (c6), using HMG-CoA reductase.
- Mevalonate is converted to Squalene (C30)
- Squalene is converted to cholesterol (C27).
Stage 1 of cholesterol biosynthesis: conversion of Acetyl-CoA to mevalonate
- Acyl CoA is converted to HMG-CoA
- HMG-CoA converted to mevalonate using HMG-CoA reductase
- This step oxidises NADPH to NADP+.
- Rate determining step, target from statins.
Statins
Competitive inhibitors of HMG-CoA reductase
Natural and synthetic statins
Natural statins
Derived from yeast
Lovastatin (mevacor)
Compactin
Pravastatin (pravachol)
Simvastatin (Zocor)
Natural statins
Atorvastatin
Fluvastatin
Reasons for transporting lipids around the body
Dietary lipids- energy production and storage in cells.
Dietary lipids—> cell membrane synthesis.
Movement of lipids from adipose to tissue for energy production.
Excretion: peripheral tissues to the liver.
Albumin
Blood protein that transports short-chain fatty acids in the blood.
Lipoprotein
Main transport of lipids in the body.
Composition:
Triacylglycerols and cholesterol esters in the central core.
Outer layer-
Amphipathic phospholipids
Cholesterol
Apolipoproteins
What lipoprotein mainly carries cholesterol?
LDL
Chylomicrons
Delivery dietary TGs to muscle and adipose tissue
Also delivers dietary cholesterol to the liver.
VLDL
Very low density lipoprotein
Transports endogenous TGs and cholesterol in the blood.
When lipid content depletes in VLDL, it becomes IDL.
LDL
Transports cholesterol from the liver to tissues
HDL
High density lipoprotein
Transports cholesterol from tissue to liver- reverse cholesterol transport.
Tangier disease
Genetic disorder that causes severe reduction of HDL in the bloodstream.
Due to mutation in ABCA1 enzyme which allows cholesterol to leave cells.
Lipoprotein lipase
Enzyme that allows the release of TG at tissues.
Found in chylomicrons and VLDL- allows them to drop TG.
ApoB-100
An apolipoprotein that is found on LDL particles.
ApoB-100 is recognised by LDL receptors in the liver and on other cells.
ApoE
An apolipoprotein found on all lipoproteins.
Recognised by the liver which takes them up for recycling.
Cholesterol uptake by cells
LDL receptors on cells recognise ApoB-100 on LDL.
This causes the LDL particle to be taken in with LDL receptors- LDL receptors are recycled.
LDL is broken down to release cholesterol in the endosome.
Increase in cholesterol uptake = decrease in cholesterol synthesis via HMG-CoA reductase
Familial hypercholesterolaemia
Genetic condition that causes a mutation in the LDL receptor or ApoB-100.
Prevents uptake of LDL, hence cholesterol.
Causes individuals with this disease to have very high serum cholesterol and increased risk of CVD.
PCSK9
A protein that binds to LDL receptors and degrades the receptors.
Prevents recycling of receptors, thus less cholesterol is taken in.
This causes higher plasma LDL-C.
