Lecture 24 - Absorption and transport of fats Flashcards
Two examples of molecules associated with fat metabolism
Triacylglycerol
Cholesterol ester
Bile salts
Bile salts solubilise fat in the gastrointestinal tract
Bile salts are synthesised from cholesterol in the liver and stored in the gallbladder as bile
Secreted into the small intestine in response to cholecystokinin
They are powerful detergents with hydrophobic and hydrophilic surfaces
Form micelles with triacylglycerols to increase surface area for digestion
What are bile acids (bile salts) made from?
Bile salts are synthesised from cholesterol
Where is bile synthesised and stored? What stimulates its secretion?
Made in the liver and stored in the gallbladder as bile
Secreted into the small intestine in response to cholecystokinin
Bile contains …
Water Bile acids Electrolytes Phospholipids Cholesterol (when this is increased it can lead to gall stones) Bile pigments i.e. bilirubin
Gastrin
Source is the stomach
Major stimulus for its production = protein containing food in the stomach, also parasympathetic nerves to the stomach
Major actions = stimulates the secretion of gastric juices
Secretin
Source is the duodenum
Major stimulus for its production = HCl in duodenum
Major actions = stimulates the secretion of alkaline bile and pancreatic fluids
Cholecytsokinin
Source is the duodenum
Major stimulus for its production = fats and amino acids in the duodenum
Major actions = stimulates release of pancreatic enzymes and stimulates the release of bile from the gall bladder
Digestion of lipids
Lipids are emulsified by bile salts to form micelles
Pancreatic lipase/colipase enzyme system binds to lipid/aqueous interface of micelle and hydrolyses triacylglycerols
Pancreatic lipase hydrolyses fatty acids at positions 1 and 3 of glycerol backbone of triacylglycerol
Smaller micelles form containing bile salts, free fatty acids, monoacylglycerol (and cholesterol)
Micelles are absorbed across intestinal cell membrane
Pancreatic lipase hydrolyses TAGs into ….
Tp free fatty acids (2 of them) and 2-monoacylglycerol (middle branch)
Bile salts solubilise ______ and assist with _______
Triacylglycerols and assist with hydrolysis
The hydrophobic face of the bile salt faces inwards whilst the hydrophilic face faces outwards to the aqueous environment and then pancreatic lipase can recognise these micelles and can come and bind and then is able to access between the bile salts to get at and hydrolyse the triacylglycerols
Absorption of products from the gastrointestinal tract into the body
The small intestine has specialised structures that create a vast surface area for absorption
These structures are called villi and microvilli (brush border is the microvilli)
Fat malabsorption
Leads to excess of fat and fat soluble vitamins in faeces
Caused by conditions that interfere with bile or pancreatic lipase secretion i.e. pancreatitis, gall bladder or liver diseases
Xenical (orlistat)
Xenical (orlistat) is a potential inhibitor of pancreatic lipase - can be prescribed to individuals who need to reduce the levels of lipid absorption in the GI tract, makes tight binding in the pancreatic lipase active site and a covalent bond is formed which inhibits the lipase so it means that lipid absorption is decreased
Overview of lipid processing in the gastrointestinal tract
Overview of lipid processing - food materials containing various types e.g. triacylglycerols, gall bladder is producing bile salts and the pancreas is supplying lipase, colipase and bicarbonate to neutralise the acid flow from the stomach, then we have bile salts forming micelle structures around the triacylglycerols and the lipase/colipase system is able to recognise this and access through the micelles bile salt structure and do the hydrolysis of the triacylglycerols and this reduces it down into 2-monoacylglycerol and 2 free fatty acids which form smaller micelle structures which are able to be absorbed across the epithelial layer and then there is a further processing event that goes on so that we now have the reformation of triacylglycerols and these are then incorported into other micelle structures called chylomicrons and these chylomicrons are able to make their way through the lymphatic system and enter the blood and then circulate through to the peripheral tissues such as the liver.
Blown up depiction of what is happening in the epithelial cells…. uptake smaller micelles containing fatty acids and 2-monoacylglycerol and a processing event occurs in the smooth ER where we get reformation of the triacylglycerols also other proteins are being produced that are accessory proteins that combine together with the triacylglycerols to generate the chylomicrons which are organised through the golgi complex and these chylomicrons are able to pass out of the epithelial cell through the lymph system and ultimately to the circulation
Lipoproteins
Help ‘solubilise’ lipids for transport in blood to tissues
Provide a ‘delivery system’ for transporting lipids into and out of cells
Apoproteins have important functions…
Structural for assembly - ApoB
Ligands for cell surface receptors (ApoE and ApoB)
Enzyme cofactors - ApoCII for lipoprotein lipase
Apoprotein - structural for assembly
ApoB
Apoprotein - ligands for cell surface receptors
ApoE and ApoB
Apoprotein - enzyme cofactors
ApoCII for lipoprotein lipase
General lipoprotein structure
Composition of lipoproteins varies depending on the purpose of the lipoprotein
Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesterol esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins
Lipoprotein purpose
A lipoprotein is a biochemical assembly whose primary purpose is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids.
Four main lipoprotein classes
Chylomicrons
Very low density (VLDL)
Low density (LDL)
High density (HDL)
Lipid transport pathways
Two major lipid transport pathways:
Exogenous chylomicron pathway (dietary fat)
Endogenous VLDL/LDL pathway (endogenously synthesised fat - fat produced in the body)
Chylomicron assembly
Triacylglycerols and other lipids combine with ApoB in the ER to form chylomicrons
Chylomicrons secreted from intestinal epithelial cells enter the bloodstream via the lymphatic system
Chylomicrons can give plasma a ‘milky’ appearance after a fat rich meal which is because of the uploading of the chylomicrons dealing with all the dietary lipids coming through the system
Lipoprotein lipase
Enzyme found on the endothelial surface
Hydrolyses TAG into lipoproteins to glycerol and fatty acids, highest actives in the heart, skeletal muscle and adipose tissue
Activated by ApoCII
Defects (by mutation) in either ApoCII or lipoprotein lipase lead to elevated levels of chylomicrons and plasma triacylglycerol (less hydrolysis in these defect presentations)
Familial ApoCII deficiency
autosomal recessive disorder in which apolipoprotein CII (apoC-II), a cofactor for LPL, is absent, the clearance of chylomicrons from the blood is greatly impaired and triglycerides (TG) accumulate in the plasma
Affects VLDL processing, defect in the ApoCII
Familial hypercholesterolaemia (FH)
Common form of hyperlipidaemia which leads to premature atherosclerosis
Caused by defect in LDL receptor gene (many different mutations)
Dominant disorder therefore heterozygotes are affected
LDL (‘bad’ cholesterol) levels 2-3 times higher than normal
Treated with ‘statins’ to lower LDL and increase HDL (‘good’ cholesterol)
Xanthomas in FH patients - fatty growths under the skin
Affects the VLDL remanant clearance stage, defect in the LDL receptor
Patient with high blood triglyceride levels can be treated with …
Tricor (fenofibrate)
VLDL
VLDL stands for very-low-density lipoprotein. Your liver makes VLDL and releases it into your bloodstream. The VLDL particles mainly carry triglycerides, another type of fat, to your tissues.
It’s considered one of the “bad” forms of cholesterol, along with LDL cholesterol and triglycerides. This is because high levels cholesterol can clog your arteries and lead to a heart attack.
Can be estimated from VLDL=(triglyceride/5)
LDL
LDL stands for low-density lipoproteins. It is sometimes called the “bad” cholesterol because a high LDL level leads to a buildup of cholesterol in your arteries.
Can be estimated from (total cholesterol - HDL - triglyceride/5)
HDL
HDL stands for high-density lipoproteins. It is sometimes called the “good” cholesterol because it carries cholesterol from other parts of your body back to your liver. Your liver then removes the cholesterol from your body.
90% of dietary fat comes from?
Triglycerides
Difference between hormone sensitive lipase and lipoprotein lipase
Hormone sensitive lipase is used during TAG mobilisation and it is activated by glucagon and adrenaline. Lipoprotein lipase is used in the exogenous and endogenous and it is activated by APOCII
