Fuel Digestion, Absorption and Storage Flashcards
Name the 3 major fuel stores.
- Glycogen – stored in muscle and in the liver
- Triacylglycerol in adipose (liver and muscle)
- Protein in muscle and all other cells, only used as a fuel in significant quantities in starvation, usually conserved until triacylglycerol in adipose tissue is depleted.
Can animals convert fatty acids to carbohydrates?
Animal cannot convert most fatty acids in carbohydrates, only when odd chain fatty acids are broken down into propionyl-CoA.
How are carbohydrates digested, absorbed and used?
Carbohydrates can be broken down into monosaccharides.
Can be absorbed directly into the blood as glucose. Glucose can then be taken up by a variety of different tissues.
Can be:
- Immediately oxidised to CO2 and water
- Used to synthesise glycogen
- Synthesised to acetyl-CoA and then used to synthesise fats, stored as triacylglycerol
How are proteins digested and used?
Proteins are broken down into amino acids. These can be:
- Directly used for protein synthesis
- Synthesis of glucose at the liver and stored as glycogen
- Can be broken down to acetyl-CoA and synthesise fatty acids, stored as triacylglycerol
- Can be synthesised into fatty acids that can be oxidised to produce CO2 and water
How are fats digested and used?
Fat can be broken down into fatty acids and glycerol, which can be stored as triacylglycerol by chylomicrons.
Can be broken down into fatty acids by lipases and be:
- Stored as triacylglycerol
- Oxidised to CO2 and water
Describe the structure of glycogen.
Linear chain of glucose molecules joined by 1-4 and 1-6 alpha glycosidic linkages.
In cells, forms spherical molecules with a glycogenin in the centre. The highly branched nature means that there are many free end for glucose to be rapidly synthesised and added on, meaning it can be very quickly hydrolysed.
What is the function of glycogenin?
Is a self-glycosylating protein – it can covalently modify itself by the addition of glucose units. These glucose units acts as a primer upon which the glycogen molecule can grow. This is essential, as glycogen synthase can only add 1 glucose at a time.
Describe the synthesis of glycogen synthesis.
UDP = activated form of glucose that acts as the glucose donor
- Glucose converted to glucose 6-phosphate by hexokinase, requiring hydrolysis of an ATP molecule.
- Glucose 6-phopshte converted to glucose 1-phopshate by phosphoglucomutase.
- Glucose 1-phosphate is converted to UDP glucose by uridine transferase, which uses UTP (uridine triphosphate) as a donor for the UDP group.
- UDP glucose transfers UDP units to glycogen to elongate the strand in glycogen synthesis.
- Branching enzyme forms alpha 1-6 glycosidic bonds.
Describe glycogen breakdown.
- Debranching enzyme breaks down the alpha 1-6 glycosidic bonds in glycogen chain.
- Glycogen strand is converted to a glycogen strand with one less unit and glucose 1-phosphate by glycogen phosphorylase, which uses an inorganic phosphate.
- Glucose 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase.
- In muscle, glucose 6-phosphate can only be used for glycolysis.
- In liver cells, glucose 6-phosphate can be converted to glucose by glucose 6-phosphatase. Glucose can then be exported by the liver.
How is glycogen metabolism controlled?
Key regulatory enzymes = glycogen synthase and glycogen phosphorylase. Are co-ordinately regulated to prevent futile cycling, meaning when one is turned on, the other is turned off.
Hormonal control:
• Insulin activates glycogen synthase and inhibits glycogen phosphorylase. Released in the fed state when glucose is abundant.
• Adrenaline and glucagon inhibit glycogen synthase and activate glycogen phosphorylase
Allosteric control but control differs in the liver and muscle due to the presence of different isoenzymes.
• Liver: when glucose and glucose 6-phosphate levels rise, glycogen synthase is activated and phosphorylase is inhibited, promoting glycogen synthesis in the fed state.
• Muscle: glycogen phosphorylase is allosterically activated by AMP and calcium ions. Calcium ion concentrations rise on contraction when ATP is required. AMP stimulated when ATP levels drop in the cell.
Name 3 glycogen storage diseases.
- Type 1 glycogen storage disease is more prevalent in Maltese dogs, due to a defect in or lack of liver glucose 6-phosphase activity.
- Type III glycogen storage disease is due to a defect in debranching enzyme. Seen in Alsatians.
- Type V seen in Chevrolet cattle and is due to a muscle phosphorylase deficiency.
How can glycogen storage diseases manifest?
- Diseases that affect the liver manifest as hypoglycaemia
* Diseases that affect muscles manifest as muscle weakness
What are the 2 types of tissue that fat is stored as triacylglycerol in and their function?
- White adipose tissue – the main lipid storage. The large spherical white adipocytes have a single lipid droplet that occupies most of the cytoplasm. Main functions are to store triacylglycerol and mobilise it during fasting or starvation.
- Brown adipose tissue – non-shivering thermogenesis. Cells contain many small lipid droplets and many mitochondria (which lead to their brown colour)
What is the function of thermogenin and where is it found?
Inner mitochondrial membrane in brown adipose mitochondria contains large amounts of uncoupler protein 1/thermogenin.
- The protein acts as a proton channel and can dissipate the proton gradient which is usually used for protein synthesis in oxidative phosphorylation. The energy dissipated by the gradient is lost as heat instead of being used for protein synthesis.
- Thermogenin is a gated channel that opens in response to noradrenaline stimulation.
Describe the process of mobilisation in white adipose tissue.
- Mobilisation of triacylglycerol by hormone sensitive lipase in lipolysis to produces 3 fatty acids and a glycerol, which both leave the cell. This is activated by glucagon and adrenaline.
- Glycerol converted to glucose in the liver and fatty acids are bound to albumin in the circulation.
- Fats can be synthesised from glucose which enters the cell via a glucose transporter. Activated by insulin.
- Glucose rapidly metabolised by glycolysis, providing acetyl-CoA for fatty acid synthesis and dihydroxyacetone phosphate for glycerol 3-phospahet synthesis, which is required for triacylglycerol synthesis and is activated by insulin.
- Acetyl-CoA can be converted to acyl-CoA by lipogenesis pathway. Activated fatty by insulin.
- Acyl-CoA and glycerol 3-phosphate are used by glycerol 3-phosphate acyltransferase to from triacylglycerol in esterification.
- Adipocytes can also uptake fatty acids produced from lipoproteins in the circulation by lipoprotein lipase. These can enter the esterification process as well for triacylglycerol storage.
Outline the key steps of lipogenesis/fatty acid synthesis.
- Export of acetyl-CoA from mitochondria to the cytosol via the citrate shuttle.
- Carboxylation of acetyl-CoA to from malonyl-CoA.
- Formation of the fatty acid by fatty acid synthase
- Further modification of fatty acid and esterification
What does citrate shuffle allow? Describe the process of citrate shuffle.
Allows acetyl-CoA in the mitochondrial matrix to leave and be used in fat synthesis in the cytosol.
- Acetyl-CoA converted to citrate by citrate synthase.
- Citrate is transported out and into the cytosol by a transporter in the inner mitochondrial membrane.
- In the cytosol, it is acted on by ATP citrate lyase and is converted into oxaloacetate and acetyl-CoA, utilising ATP hydrolysis.
- Acetyl-CoA sent back into the mitochondria. Oxaloacetate is converted to malate by the cytoplasmic form of malate dehydrogenase, oxidising an NAD molecule.
- Malate is decarboxylated by malic enzyme to form pyruvate, reducing an NADP. NADPH used in fat synthesis.
- Pyruvate can enter the mitochondria via a specific transporter protein in the inner mitochondrial membrane.
- Here, pyruvate is properly carboxylated to re-form oxaloacetate, utilising ATP hydrolysis.
What is the role of malonyl-CoA?
Malonyl-CoA is the intermediate that provide most of the carbon atoms required for the synthesis of fatty acids in the reactions that are catalysed by fatty acid synthase.
Describe the synthesis of palmitate.
- Fatty acid synthase binds 1 acetyl-CoA to 1 malonyl-CoA.
- The malonyl group binds to a domain called the acyl carrier protein/ACP domain.
- Malonyl-CoA then acts as a donor for all subsequent carbon atoms in the synthesis of palmitate.
- Palmitate can be further elongated and desaturated in the smooth endoplasmic reticulum.
The overall reaction requires 14 NADPH molecules.
Describe the action of fatty acid synthase to produce 16 C palmitate.
- Acetyl-CoA donates an acetyl group and malonyl-CoA donates a malonyl group.
- These both bind to the fatty acid synthase enzyme.
- These groups then condense to form an acetoacetyl group and a CO2 molecule is lost.
- Acetoacetyl group undergoes reduction, dehydration and a further reduction to form a butanyl group, still attached to the fatty acid synthase enzyme.
- Butanyl group can be further elongated with 2 carbon additions from addition melanoma CoA molecule.
- This continues until 16 carbon palmitate is produced.
How is fatty acid synthesis controlled?
Acetyl-CoA carboxylase: is subject to allosteric and hormonal control. This controls the production of malonyl CoA.
Pyruvate: pyruvate supply and activity of pyruvate dehydrogenase.
Hormonal and nutrient control of gene expression affects the expression of enzymes:
• Acetyl-CoA carboxylase
• Fatty acid synthase
• Pentose phosphate pathway enzymes
What is the function and source of cholesterol?
Cholesterol is used in cell membranes, steroid hormones, bile acids, vitamin D.
Sourced either from diet or endogenous.
Excess is secreted in bile.
Describe cholesterol synthesis and its control.
Endogenous synthesis: synthesised from acetyl-CoA, occurring in most tissues, especially the liver.
Rate limiting enzyme is HMG-CoA reductase.
Short term control:
• Allosterically inhibited by cholesterol
• Inhibited by glucagon, activated by insulin
Long term control: expression of the enzyme is inhibited by cholesterol.
What is produced when pancreatic lipase acts on the micelles produced from fat emulsification?
Triacylglycerol, which can produce fatty acids, diacylglycerol and monoglycerols
Cholesterol esters, which can produce cholesterol and fatty acids
Phospholipids, which can produce lysophospholipids and fatty acids
Describe lipid absorption.
- Enterocytes uptake mixed micelles and unpackage them.
- Lipid components are solubilised by binding to fatty acid binding protein, which helps to stabilise the hydrophobic molecules.
- These complexes move to the SER, where triacylglycerol is re-synthesised.
- These move through the Golgi apparatus and are packaged with proteins, cholesterol and phospholipids into chylomicrons.
- Chylomicrons are secreted into the lacteals before they enter the lymphatic system, so do not enter the blood directly.
- Medium or short chain fatty acids can actually enter the cell by simple diffusion.
- Very small fatty acids dop in fact enter the blood directly.
State the classes of lipoproteins in order of increasing density.
- Chylomicrons CM
- Very low density lipoproteins VLDL
- Intermediate density lipoproteins IDL
- Low density lipoproteins LDL
- High density lipoproteins HDL
Briefly describe the composition of the lipoprotein classes.
Chylomicrons have 90% triglyceride. Triglyceride decreases as density increases.
Cholesterol and phospholipid content generally increase with density, except LDL being greatest in cholesterol and a lower phospholipid content than the trend.
HDL has greatest protein content at 50%. Protein increases as density increases.
What are the functions of each class of lipoprotein?
- CMs are involved in the transport of lipids derived from the diet – exogenous.
- VLD, IDL and LDL transport endogenously synthesised triacylglycerol and cholesterol from the liver and other tissues – endogenous.
- HDL cats as a reservoir for a number of apoproteins and a role in cholesterol transport.
State 4 roles of apoproteins.
- Structural
- Ligands for receptors
- Activators of enzymes
- Some are loosely associated with lipoproteins and can be transferred between them
Describe lipoprotein metabolism.
- Chylomicrons are acted on by lipoprotein lipase, which breaks down the triacylglycerol core, hydrolysing triacylglycerol.
- This liberates free fatty acids, which are taken up by tissues.
- This process repeats and the chylomicrons gets smaller as its triacylglycerol core is hydrolysed.
- Eventually forms a chylomicron remnant, which is then taken up by the liver.
- Lipids that are synthesised in the liver are packaged and exported as VLDL particles.
- These enter the circulation and are acted upon by lipoprotein lipase and their triacylglycerol content is diminished. They are transformed from VLDL to IDL to LDL.
- LDL can be taken up by peripheral tissues, which helps deliver cholesterol to these peripheral tissues.
- Or some are recycled back to the liver in endogenous pathway.
Describe the pathway of exogenous lipid transport.
- The nascent (first enter the blood and contain B48 and A proteins) chylomicrons enter the circulation at the thoracic duct, the site of turbulent blood flow that ensures that the chylomicrons are mixed well with blood.
- Chylomicrons pick up additional apoproteins CII and E from HDL to become fully mature.
- As the chylomicron move through the tissue capillary bed, they encounter lipoprotein lipase, which is expressed on the surface of blood vessel endothelial cells.
- Lipoprotein lipase is activated by the lipoprotein CII and it hydrolyses the triacylglycerol within the particle, forming free fatty acids and glycerol, which can be take up by cells, such as muscle and adipose. In muscle, free fatty acids will be used for oxidation. In adipose tissue, the free fatty acids will be stored as triacylglycerol molecules.
- Chylomicrons are diminished in size and are now called chylomicron remnants because the triacylglycerol core has been hydrolysed.
- Chylomicron remnants can interact with HDL and there will be some movement of lipoproteins back to the HDL particles.
- The remnants can then be taken up by hepatocytes via receptor mediated endocytosis.
Describe the pathway of endogenous lipid transport.
- Liver packages newly synthesised triacylglycerol as VLDL particles with cholesterol and apoprotein B100 to form nascent VLDL particles.
- In the circulation, they can interact with HDL and pick up apoprotein CII and apoprotein E to form the mature VLDL particle.
- Mature VLDL particles will interact with LPL on the surface of the endothelial cells in the capillary bed. Lead to breakdown of the triacyclglycerol core, leading to a reduction in size of the VLDL particle until it is VLDL remnant.
- The VLDL remnant can interact with HDL particles. There is some movement of apoproteins back into the HDL particle.
- This movement will lead to the formation of IDL particles.
- IDL particles will continue to interact with HDL in the circulation until they become LDL particles.
- LDL particles can be taken up by peripheral tissues through interaction with LDL receptors in receptor mediated endocytosis.
- The cholesterol that from a large part of the LDL can be esterified the cholesterol acyl transferase to form cholesterol esters.
- IDL and LDL returned to the liver and recycled by receptor mediated endocytosis.