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Fat Metabolism Notes

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FAT METABOLISM Body energy supplies
-Fat- 10,000g ; 90,000 kcal ; 73%
-liver glycogen ; 70g, 280 kcal ; 0.2%
-muscle glycogen ; 225; 900kcal ; 0.75%
-blood glucose; 15g ; 60kcal; 0.05
-Protein 7500g; 30000, 23%
Intake per day FAT- 60g, 600 kcal CARBOHYDRATE - 200g, 800 kcal PROTEIN- 70, 300 kcal Advantages and disadvantages of using fat as a metabolic fuel
-the stores of fat can be completely depleted without interfering with body function, unlike protein supplies
-the fat can be readily mobilised and there is a rapid turnover
-double the energy per gram of dryweight than glycogen and has low hydration level due to its hydrophobic nature
-used as an energy source for tissues that require high sustained energy requirement- heart and renal cortex
-disadvantage- the lipids are non polar, and insoluable in water- need special transport systems
-release of energy from fat is relatively slow compared to glycogen as there are a large number of metabolic processes needed before it can enter the TCA cycle
-35% of the total energy production per day

Assimilation of dietary fat
-Dietary lipids are in the form of triglycerides-non polar molecules that are insoluable in water- in the lumen they form large lipid droplets- inaccessible to pancreatic lipases
-bile salts are secreted by the liver- emulsify the large lipid droplets into smaller lipid droplets that have a lower surface tension and a greater surface area. Bile salts are amphiatic molecules that consist of phospholipids and cholesterol - sodium glycocholate and sodium tarocholate- hydrophobic ends of the salts interact with the hydrophobic triglycerides, whilst the hydrophilic ends interact with the water
-the coating prevents the small lipid droplets from reassociating and ester bond is positioned on the surface of the lipid droplet- increases the likelihood of the pancreatic lipases hydrolysing the lipids into fatty acids and monoacylglycerol
-fatty acids and glycerol- non polar and relatively insoluable in water- associated with bile salts to form micelles. Once these structures reach the enterocytes, they break down and the fatty acids and monoacylglycerides are transported across the enterocytes via membrane transport proteins. Enterocytes
-triglycerides are resynthesised from the fatty acids and glycerol molecules.
-In order for the triglyceride to be transported in the aqueous environment of the blood plasma, the triglycerides are enclosed in a lipoprotein to form chylomicrons. The chylomicrons-synthesised in the enterocytes- consist of a monolayer of phospholipids and have apolipoproteins (apolipoprotein B-48) inserted- protein have hydrophobic domains that insert into the core and hydrophilic domains that are exposed at the surface. Apolipoproteins form cofactors for enzymes and are ligands for receptors
-chylomicrons are too big to enter the blood capillaries so the enter the lympathic vessels which drain into large veins- thel lipids bypass the liver Triglycerides synthesised in the liver Very low density lipoproteins transport high density triglycerides to the adipose tissue Hyperlipidaemia
-causes: primary hyperlipidaemia is mostly due to genetics- e.g lipoprotein lipase deficiency / mutation in the LDL receptor
-abnormally elevated levels of any lipids (cholesterol/cholesterol esters/phospholipids/triglycerides) or elevated plasma triglyceride in very low density lipoproteins or increased low density lipoproteins

-symptoms: fat deposits in the skin/tendons, swelling of organs, obstruction of blood vessels in heart and brain.
-Due to cells being unable to absorb fatty acids, there is increased oxidation of glucose- increased production of NADPH, NADH, acetyl CoA. This stimulates hepatic fatty acid and triglyceride synthesis and suppression of fatty acid oxidation. TREATMENT: prevent hypoglycaemia- so in babies frequent high glucose feeds during the day and nocturnal nasogastric glucose infusion overnight. In children and adults-oral uncooked corn starch, reduced intake of fructose/galactose (these sugars are taken up by the liver and stored as glycogen) Adipose tissue
-Chylomicrons are broken down by lipoprotein lipase on the surface of endothelial cells
-Peripheral tissues have membrane bound lipases which break down the triglycerides into free fatty acids and monacylglyercides- products taken up into cell via diffusion and mediated transport
-The glycerol and the remanants of the lipoprotein flow in the circulation to liver where they are metabolised- glycerol doesn't enter as the adipose tissue doesn't have kinase enzymes to activate it
-the fatty acids are esterified to TG by combining them to glycerol-3-phosphate.uniform large lipid droplet- completely exclude water
-lipid droplet surrounded by a thin monolayer of phospholipids and proteinsperilipin Transport of cholesterol: mention in Lipid transport essays
* Transport of Cholesterol: Low density lipoproteins transport cholesterol to cells in the body. The very low density lipoproteins that have lost their Triacylglycerol become more dense, and are remodelled in the liver to LDL-cholesterol is used in cells for synthesis of steroid hormones, used in membranes- LDL bind to a specific LDL receptor and is internalised by endocytic vesicle
*HDL: involved in reverse cholesterol transport- excess cholesterol is eliminated from the body via the liver, which secretes cholesterol in liver or converts it into bile salts. Pathology: Familial hypercholesterolemia-very high levels of LDL, defect in LDL receptors-so LDL is not cleared from circulation, also as cholesterol can't enter cells there is no negative feedback suppression of cholesterol synthesis in the liver

-Lipid profile-measures total levels of cholesterol, LDL cholesterol, HDL cholesterol and triglycerides- Dyslipidemia-high levels of LDL cholesterol greatly increases the risk of atherosclerosis as they contribute to plaques Treatment: Statins: Inhibit HMG-CoA reductase-rate limiting enzyme in cholesterol synthesisinhibiting cholesterol synthesis decreases circulating LDL-due to reduced levels of cholesterol in hepatocyte

Mobilisation in adipose tissue
-lipase activity in adipose tissue is regulated by glucagon, adrenaline, noradrenaline, adrenocorticotrophic hormone. The hormones bind to G protein coupled receptors and activate adenylate cyclase, increasing the intracellular concentrations of cyclic AMP and activating protein kinase A.
-the protein kinase A phosphorylates perilipin- restructures the fat droplet so the TG are more accessible to mobilisation
-The protein kinase A phosphorylates triacylglycerol lipase, activating it to break down triacylglycerides- releasing diacylglycerol and fatty acids
-diacylglycerol lipase breaks down diacylglycerol into free fatty acid and monoacyl glycerol
-monacylglycerol lipase- completes the mobilisation of fatty acids
-the released fatty acids leave the cell and are transported to peripheral tissues bound to albumin in the plasma.- hypoalbuminemia-not enough albumin, no transport of fatty acids-can't enter cells-insulin activates a phosphotase which dephosphorylates the lipase thus inactivating it Plasma levels of NEFA (non esterified fatty acids)
-fatty acids are at fairly low concentrations under normal conditions (sub mM)- 0.30.6
-during starvation levels rise to 1Mm
-excerise -Maximum of 2 mM

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