Lipids Flashcards
How can lipids be classified?
Fatty Acid Derivatives:
- fatty acids
- triacyclglycerols (fuel storage and insulation)
- phospholipids (components of membranes and plasma lipoproteins)
- Eicosanoid ( local mediators)
Hydroxy-methyl-glutaric acid derivatives (C6 compound):
- ketone bodies (C4, water soluble fuel molecules)
- cholesterol (C27, membranes and steroid hormone synthesis)
- cholesterol esters (cholesterol storage)
- bile acids and salts (C24, lipid digestion)
Vitamins:
- A
- D
- E
- K
All fat-soluble
How are dietary triacylglycerols processed by the body?
- hydrolysed by pancreatic lipase in the small intestine to release glycerol and fatty acids. (bile salts and cofactor protein colipase required)
- recombination of fatty acids and glycerol into TAG’s in small intestine
- In intestinal epithelial cell, TAG’s synthesised into chylomicrons
- chylomicrons travel via lymphatic system
- can be released into blood where they can enter tissues for fatty acid oxidation or into adipocytes for storage
How are triacylglycerols stored?
- In adipocytes
- TAGs are hydrophobic and therefore stored in an anhydrous form in adipose tissue
utilised in prolonged exercise, starvation, during pregnancy.
mobilisation under hormonal control
List the three ketone bodies
- Acetoacetate
- Acetone
- b-Hydroxybutyrate
Describe the synthesis of ketone bodies
- synthesised by liver mitochondria from acetyl-coA
- Acetoacetate formed from acetyl-coA via HMG-CoA lyase
- Acetone formed from Acetoacetate by spontaneous decarboxylation
- b-hydroxybutyrate formed from acetoacetate
When the insulin/glucagon ratio is high, i.e. fed state:
- HMG-CoA lyase is inhibited
- HMG-CoA reductase stimulated and cholesterol synthesised
Describe the clinical relevance of ketone body concentration in the blood
Normal plasma ketone body concentration is under 1 mM
Starvation 2-10 mM (physiological ketosis)
Untreated Type 1 diabetes > 10mM (pathological ketosis)
Explain the process of beta oxidation of fatty acids
- sequence of reactions that oxidises the fatty acid and removes the C2 unit (acetate) until only two carbons remain.
- requires mitochondrial NAD+, FAD, oxygen (required for stage 4 (oxidative phosphorylation/ET) of catabolism to re-oxidise the NADH and FAD2H formed)
- no direct synthesis of ATP by the pathway.
- all the intermediates linked to coenzyme A
- C-atoms of the fatty acid are converted to acetyl~CoA
Explain the process of lipogenesis
- occurs mainly in liver
1) glucose converted into pyruvate in cytoplasm
2) pyruvate enters mitochondria and forms acetyl-CoA and Oxaloacetate
3) They condense to form citrate
4) Citrate moves into cytoplasm and cleaved back to Acetyl-CoA and Oxaloacetate
5) Acetyl-CoA carboxylase produces Malonyl-Coa from acetyl-CoA
6) Fatty acid synthase complex builds fatty acids by sequential addition of 2 carbon units provided by malonyl-CoA - NADPH from pentose phosphate pathway provides reducing power for building up the fatty acids
- ATP regulated.
- Key regulator is Acetyl-CoA carboxylase; insulin stimulates and glucagon inhibits (covalent dephospho rylation)
What is the structure of phospholipids?
- Polar head (hydrophilic)
- linked to a phosphate
- which is linked to glycerol
- with two fatty acid tails (hydrophobic)
Describe the structure of lipoproteins
- Phospholipid monolayer with small amount of cholesterol
- Peripheral apolioproteins (e.g apoC, apoE)
- Integral apolioproteins (e.g apoA, apoB)
- Cargo consisting of triacylglycerol, cholesterol esters, fat soluble vitamins
What are apolioproteins?
- Each class of lipoprotein particle has a particular complement of associated proteins (apolioproteins)
- Six major classes (A, B, C, D, E and H)
- apoB (VLDL, IDL and LDL) and apoAI (HDL) important
- peripheral; c and e
- integral; a and b
They have two roles:
Structural- Packaging water insoluble lipid
Functional- cofactor for enzymes, ligands for cell surface receptors
What are the classes of lipoprotein?
From least to most dense:
- chylomicrons
- VLDL’s
- IDL’s
- LDL’s
- HDL’s
What are hyperlipoproteinaemias?
Raised plasma level of one or more lipoprotein classes. Caused by either:
1) overproduction
2) underremoval
6 main classes
Defects in:
Enzymes
Receptors
Apoproteins
see notes
What is an adipocyte?
- Large lipid droplet (mainly TAG and cholesterol ester)
- Cytoplasm and organelles pushed to edge
- Typical adipocyte is around 0.1mm in diameter however cells expand as more fat added
- Average adult has around 30 billion fat cells weighing 15kg
- Can increase in size about fourfold on weight gain before dividing and increasing total number of fat cells
Discuss the importance of cholesterol in the body
- Some cholesterol obtained from diet but most is synthesised in liver
- Essential component of mebranes (Modulates fluidity)
- Precursor of steroid hormones: cortisol, aldosterone, testosterone, oestrogen
-Precursor of bile acids
Transported around body as cholesterol ester
Describe chylomicron metabolism
- Chylomicrons loaded in small intestine and apoB-48 added before entering the lymphatic system
- Travels to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood
- apoC binds to lipoprotein lipase (LPL) on adipocytes and muscle. Released fatty acids enter cells depleting chylomicron of its fat content.
- When triglyceride reduced to around 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
- Chylomicron remnants return to liver. LDL receptor on hepatocytes binds remnant (via receptor mediated endocytosis). Lysosomes release remaining contents for use in metabolism
Describe VLDL metabolism
- VLDL made in liver for purpose of transporting triacylglycerols (TAG’s) to other tissues
- Apolioprotein apoB100 added during formation and apoC and apoE added from HDL particles in blood
- VLDL binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose and starts to become depleted of triaglycerol
- In muscle the released fatty acids are taken up and used for energy production
- In adipose the fatty acids are used for re-synthesis of triacyclglycerol and stored as fat
Describe IDL metabolism
- As triacylglycerol content of VLDL particles drops some, VLDL particles dissociates from the LPL enzyme complex and return to liver
- If VLDL content depletes to around 30%, the particle becomes a short lived IDL particle
- IDL particles can also be taken up by liver or rebind to LPL enzyme to further deplete in TAG content
- Upon depletion to around 10%, IDL loses apoC and apoE and becomes an LDL particle (high cholesterol content)
What are the functions of LDL’s?
-Primary function of LDL is to provide cholesterol from liver to peripheral tissues.
Describe how LDL’s enter cells
-Receptor mediated endocytosis
-Cells requiring cholesterol express LDL receptors on plasma membrane
-apoB-100 on LDL acts as a ligand for these receptors
Receptor/LDL complex taken into cell by endocytosis into endosomes
-Fuse with lysosomes for digestion to release cholesterol and fatty acids
-LDL-Receptor expression controlled by cholesterol concentration in cell
Describe the synthesis of HDL’s
- Nascent HDL synthesised by liver and intestine (low triaglyceride levels)
- HDL particles can also “bud off” from chylomicrons and VLDL as they are digested by LPL
- Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL.
Describe HDL’s functions
- Reverse Cholesterol Transport from cholesterol-laden cells and return it to liver
- reduces likelihood of foam cell and atherosclerotic plaque formation
- ABCA1 protein within cell facilitates transfer of cholesterol to HDL. Cholesterol then converted to cholesterol ester by LCAT.
- HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
What are the clinical signs of hypercholesterolaemia?
Xanthelasma- Yellow patches on eyelids
Tendon Xanthoma- Nodules on tendon
Corneal Arcus- Obvious white circles around eye. Common in older people but a sign of hypercholesterolaemia in the young.
Describe how raised levels of LDL’s can cause atherosclerosis
1) Oxidised LDL’s recognised and engulfed by macrophages
2) Lipid laden macrophages called foam cells accumulate in intima of blood vessel walls to form a fatty streak
3) Fatty streaks can evolve into atherosclerotic plaque which grows and encroaches on lumen of artery (angina)
4) Rupture triggers acute thrombosis by activating platelets and clotting cascade
