Fat Metabolism Flashcards
Describe digestion of triacylglycerol
-Intestine
-Broken down by interaction with bile salts, amphipathic (hydrophobic and hydrophilic)= micelles
-Catalysed by lipase enzyme secreted by pancreas
=fatty acids (10% pass straight through portal system to liver, majority re-esterified to triacylglycerol) and monoacylglycerol
-Orlistat= inhibitor of lipase
How is triacylglycerol transported around the body?
Chylomicrons
Also contain phospholipids and proteins, cholesterol, fat-soluble vitamins A, D, E and K
-Travel in lymphatic system, enter blood through thoracic duct
-Plasma lipoproteins
=Hydrophobic core of triacylglycerol and acyl-cholesterol (cholesterol esterified with single fatty acid)
=Surrounded by hydrophilic components (apoproteins, cholesterol and phospholipids)
How are chylomicrons degraded?
- Collect apoprotein C-II and from another plasma lipoprotein HDL
- Activates enzyme to degrade them= lipoprotein lipase, exposed on outside of endothelial cells
- Hydrolyses triacylglycerol to fatty acids and glycerol
- Free fatty acids oxidised or converted to triacylglycerol
- Chylomicron remnants travel to liver
Describe how acetyl CoA is involved in fatty acid synthesis
- Carbohydrate input, metabolised by glycolysis and oxidation of pyruvate to acetyl-CoA
- Catalyst acetyl-CoA carboxylase carboxylates acetyl-CoA to malonyl-CoA
- Co2 comes from carbonate and process requires ATP
- -Intermediate is enzyme with a bound CO2 and bound to prosthetic group biotin (vitamin)
How is acetyl-CoA carboxylase regulated?
- Inhibitor of fatty acid oxidation (as well as malonyl-CoA)
- Regulated by hormonal and allosteric factors
- Exists in active and inactive forms (phosphorylated form, promoted by glucagon and AMP-activated protein kinase)
- Activation by dephosphorylation, promoted by insulin
What is the fatty acid synthase complex?
-Multi-enzyme complex
-2 identical subunits
-Fatty acid synthase primes (attachment of acetyl group from acetyl-CoA onto a cysteine side-chain)
-Loads (transfer a malonyl group from malonyl-CoA onto another sulfhydryl group onto phosphopantotheine- a vitamin and prosthetic group on enzyme)
-Condensation reaction= acetyl group transferred onto malonyl group, CO2 lost and drives equilibrium of reaction, leaving 4C oxo-acid attached to phosphopantotheine, requires saturated fatty acid
-Carbonyl group reduced to hydroxy acid (water eliminated) and reduced again to 4C saturated fatty acid by reduced NADP
-4C acid elongated, transferred back to initial cysteine
-Enzyme reloaded with another malonyl CoA
=Long chain fatty acids, 16C
Describe hormonal control of triacylglycerol synthesis
Insulin= uptake of glucose into fat and muscle, activates pyruvate dehydrogenase so acetyl-CoA formation, promotes reutilization of citrate
Glucagon inhibits oxidation of glucose in glycolytic pathway to pyruvate, inhibits acetyl-CoA carboxylase
Examples of unsaturated fatty acids
Oleic acid
Linoleic acid
Linolenic acid
Arachidonic acid
Describe the fatty acid desaturase system
- Formation of double bonds in the removal of 2 hydrogens, reduces oxygen to water
- Other oxygen atom reduced by reduced NAD
- Electrons from reduced NAD passed along electron transport chain containing flavoprotein, a haemoprotein, cytochrome b5 and iron-containing protein, the desaturase
- Different desaturase introduce double bonds at carbons 4,5,6 or 9 (not past nine- if so, essential as cannot be synthesised)
Describe mobilisation of triacylglycerol in adipose tissue
- Hydrolysis, free fatty acids available for fuel
- Hydrolysed by hormone-sensitive lipase
- Activated by adrenaline, glucagon or growth hormone, inhibited by insulin
- One fatty acid off triacylglycerol
How are non-esterified fatty acids transported and taken up?
- Low solubility, capable of diffusing through biological membranes
- Transported bound to serum albumin
- Aided by transporters
- Sequestered by fatty-acid binding protein, binds them tightly
- Once in cells, to prevent leakage out attached to coenzyme A
- Esterified on the sulfhydryl group on coenzyme A (fatty acid activation, requires ATP, hydrolysed to AMP and pyrophosphate)
Describe the structure of cholesterol
- 27C
- Component of membranes= sits in bilayer alongside phospholipids and proteins
- Precursor of bile acids and bile salts
- Precursor of various steroid hormones (glucocorticoids, mineralocorticoids, sex hormones)
Describe synthesis of cholesterol
- Acetyl-CoA x2= acetoacetyl-CoA, + another acetyl CoA= hydroxymethyl glutaryl-CoA
- Occurs in cytoplasm
- Rate limiting step= reduction of HMG CoA to mevalonate
- Then 5C, joined together to make 15C, x2= squalene, linked up to form cholesterol, with 3 Cs removed to shorten side chain
- Process regulated by level of HMG CoA reductase activity
- AMP-activated protein kinase inhibits it, as well as phosphorylation
What are the drugs that interfere with cholesterol synthesis?
-Statins= inhibitors of HMG-CoA reductase
=simvastatin, lovastatin, atorvastatin
=Reduce the level of endogenous cholesterol synthesis by inhibiting de-novo cholesterol synthesis
-Cholestyramine= oldest, ion-exchange resin which absorbs bile acids, traps in intestine to increase excretion
-Plant sterols like Benecol= inhibit uptake of cholesterol in intestine, in synthetic margarines
-Fibrates= lower triacylglycerol in plasma by increasing rate of uptake of LDL into liver
Describe synthesis of bile acids
-7-alpha hydroxyl group added by cholesterol 7-alpha hydroxylase
-Further hydroxylation and shortening of side chain
-Oxidation of side chain, carboxyl group at end of side chain
=amphipathic biological detergent
-Two primary bile acids= cholate and chenodeoxycholate
