L16 Lipid Metabolism Flashcards
What are the different roles of fats?
- Incorporation into cell and organelle membrane - particularly phospholipids and cholesterol
- Essential fatty acids (ω-3, ω-6 for example) are precursors for hormones known as eicosanoids (prostaglandins, leukotrienes, thromboxane)
Cholesterol is in important fat. It is required for: bile salts; steroid hormones (androgens, oestrogens, Progestogens, Mineralocorticoids - like aldosterone, Glucocorticoids - such as cortisol); membranes to alter the fluidity and as a precursor for Vitamin D.
- Essential fatty acids (ω-3, ω-6 for example) are precursors for hormones known as eicosanoids (prostaglandins, leukotrienes, thromboxane)
What is the function of omega 3 and omega 6?
Omega-6 fats are derived from Linoleic acid. These produce various prostaglandins and thromboxanes and various other things. The breakdown of omega-3 produces mildly inflammatory molecules and anti-inflammatory molecules. The breakdown of omega-6 on the other hand produces greatly inflammatory molecules and anti-inflammatories. This is why we need to increase omega-3 in our diet to ensure the balance in these types.
How are fats absorbed?
When we have digested and absorbed fats at the brush border of the small intestine, they are taken up into the smooth ER and there are proteins e.g. ApoB-48 needed for chylomicron formation. The triglycerides formed in the SER and the protein are processed in the Golgi to produce chylomicrons and released into lymph. This enters the circulation via the thoracic duct into the subclavian vein. Fats do not pass directly from the GI tract to the liver.
How are lipids transported around the body?
Fats are taken in from the intestines and released as chylomicrons. These then travel around in circulation. In the walls of capillaries, there is lipoprotein lipase which breaks down triglycerides into free fatty acids and glycerol which can then be taken up into adipose tissue where they can be stored or peripheral tissue for energy. The chylomicrons return to the liver; phospholipids and cholesterol that are taken in the diet go back to the liver in the chylomicron remnants. Dietary cholesterol and synthesised cholesterol, together with fats synthesised in the liver are released from the liver in VLDL. These deliver triacylglycerols to tissue. As they become more and more depleted as triacylglycerol’s, they become smaller and become LDL which contain cholesterol.
HDL is released empty from the liver and collects excess cholesterol from cells which have excess. They can transfer this to LDL which take it to cells that need it or take it back to the liver.
Why can fats not be used by the brain?
They cannot pass across the blood brain barrier.
What is the inhibitor of the cartintine transport system?
Malonyl CoA – prevents synthesis and degradation of fatty acids at the same time.
What is beta oxidation? Where does it take place?
Mitochondria - There is a series of reactions which remove 2 carbons (acetyl-CoA) from the end of the C16. Each turn gives Acetyl-CoA, FADH2, NADH + H+. Each acetyl CoA is fed into Krebs cycle – producing more NADH/FADH – in its turn fed into etc. Large amount of ATP produced – compare 36 from complete oxidation of glucose..
What is the role of carnitine?
First step requires energy – ATP to AMP – priming step (from glycolysis) Fats are attached to CoA to make an acyl CoA.
This occurs in cytosol, then FA-CoA needs to be transported into mitochondria
If over 12C use carnitine transport –
3 steps –
1. FA CoA released from CoA, and transferred to carnitine. Carnitine palmitoyl transferase I catalyses this. Occurs on outer mitochondrial membrane.
2. Fatty acyl carnitine transferred across inner mitochondrial membrane by carnitine acylcarnitine translocase – FA-carnitine transported in exchange for free carnitine.
3. FA transferred back to CoA.
This transfer is a controlled step – malonyl CoA is early metabolite in FA synthesis pathway – so prevents cycling.
How is beta oxidation controlled?
Fatty acid oxidation in largely regulated by access of fatty acids to the mitochondria – this is controlled by the concentration of malonyl CoA
At the beginning of fatty acid synthesis, acetyl CoA is converted to malonyl CoA by acetyl-CoA carboxylase. High [malonyl CoA] inhibits carnitine acyl-transferase-1. This means that you cannot have a cycle of making fats and breaking them down. This would be inefficient.
This ensures that fatty acid breakdown is inhibited when energy is plentiful.
How are ketone bodies formed?
2 Acetyl CoA are converted to acetoacetyl CoA. Another acetyl CoA joins on to form HMG CoA. This is then converted to acetoacetate. This splits into acetone and 3-hydroxybutyrate.
What are sources of cholesterol?
From the diet and synthesis (mainly in the liver and intestine).
How is cholesterol taken up by the cell?
Once in the blood in the form of LDL, it is taken up by receptor-mediated endocytosis. ApoB is found on LDL and binds to the LDL receptor on the outside of the cell. This lead to the formation of a clathrin coated pit. The LDL together with the receptors are internalised in the cell in the clathrin coated vesicle. The clathrin is recycled forming an endosome with a relatively low pH. The LDL receptor bud off and return back to the cell surface and so are recycled. The endosome fuses with a lysosome which contain enzymes to break down molecules. Cholesterol is released from the LDL into the cell. It is esterified and stored as droplets as cholesterol esters. The amount of cholesterol in the cell determines the rate of LDL receptor synthesis. This underpins cholesterol in the form of LDL building up in the blood stream.
Detail cholesterol synthesis.
- Acetyl CoA to HMG-CoA which is converted to mevalonate (C6).
This occurs in cytosol and smooth endoplasmic reticulum- Mevalonate to phosphorylated isoprene units (C5) (activation step) - addition of pyrophosphates requires ATP keeps the molecule soluble to allow it to continue along the metabolic pathway
- Polymerise 6 isoprene units to form C30 chain (squalene)
- Cyclisation to form ring structure (lanosterol) then cholesterol
How is the synthesis of cholesterol controlled?
Cholesterol synthesis is controlled by:
- Cholesterol levels - High levels of cholesterol inhibit further synthesis
- Energy levels
Insulin increases synthesis – insulin signals energy availability, glucagon inhibits to save the energy for other things
Activity of HMG CoA reductase is controlled by phosphorylation – enzyme inactivated when energy levels low – insulin and glucagon mainly act here. The main control for cholesterol synthesis is the longer term control of how much HMG-CoA reductase is produced.
What is SREBP? What is cholesterols effect on SREBP?
Sterol regulatory binding protein - When cholesterol levels in the ER membrane fall, it sets off a chain of reactions which cause the release of a protein SREBP from the membrane. This protein moves to the nucleus, binds to a sterol response element on the DNA coding for certain genes, including HMG CoA reductase, and the LDL receptor. This increase transcription, leading to more mRNA, more translation more enzyme and more cholesterol. In high levels of cholesterol, the protein is prevented from being released. This maintains the level of cholesterol at the level required for the cell.
