Case 12- vitamin absorption Flashcards
Re-esterification
Only done to long-chain FAs (12C+) and the 2MG obtained from TAGS
Re-esterification of TAG
2 ATP molecules are consumed.
• Activation of Long Chain FA by addition of CoA by the enzymes Fatty Acyl CoA synthetase, ATP is required.
• 2-Monoacyl glycerol +FA-CoA are conjugated to form Di-acyl glycerol (DAG) by the enzyme Monoglyceride acyltransferase (MGAT)
• DAG is then covalently attached to another FA-CoA by the enzyme Diglyceride acyltransferase (DGAT)
Re-esterification of Cholesterol
1 ATP is consumed
• Cholesterol + FA-CoA → Acyl-Cholesterol + CoA
By the enzyme Acyl-CoA cholesterol acyltransferase (ACAT)
Synthesis of lipids
Most lipid synthesis is at the SER. The lipids once formed move to RER where they form lipid droplets surrounded by phospholipids and a single copy of the protein, apolipoprotein B48. They are formed by Microsomal Triglyceride Transfer Protein (MTP or MTTP).
Where are lipids secreted into
The apolipoprotein called Chylomicrons are secreted into the lymphatic system. TAG and cholesterol from the diet bypass the liver.
Clinical significance of lipid metabolism
- Blockage in the common bile duct can stop pancreatic lipase and cholesterol esterase.
- CF can reduce pancreatic function, so the diet will need to be modified with more short chain fatty acids.
- Defects in lipid digestion will affect fat soluble vitamins. I.e. defects in vitamin K increase prothrombin time.
- Bile acid sequestrants (drugs)- reduce uptake of cholesterol by preventing reabsorption of bile salts, so more is excreted.
Passive uptake of fats
Uses transport proteins
Is rate limiting
The unstirred layer has an acidic pH due to H+ ions being pumped in to it
Fatty acids get protonated by this layer so become uncharged
Now they can just passively diffuse through the non-polar hydrophobic environment
Active uptake of fats
There are transport proteins for longer chain fatty acids
When fatty acids enter the cell they must be removed to maintain the gradient
We achieve this be re-esterifying TAGs
Drugs that affect lipid absorption- Orlistat
- inhibits gastric and pancreatic lipases
- fats can no longer be absorbed
Drugs that affect lipid absorption- Ezetimibe
- blocks NPC1L1 so inhibits cholesterol absorption
Vitamins
Are used as co-enzymes. They are essential apart from vitamin D which we make ourselfs
Classification of vitamins
Water soluble (C,B) or fat soluble (A, D, K, E)
B-complex vitamins
Water soluble vitamins
Vitamins involved in energy production / haematopoesis
Include C/B1/B2/B3/B12/folic acid etc
Vitamin B1 (thiamine) deficiency
Responsible for the conversion of pyruvate to acetlycoA
Therefore essential in energy production
Deficiency leads to Wernicke-Korsakoff syndrome i.e. a brain disorder, causing confusion/visual problems/lethargy
Causes Beriberi disease
Vitamin B9 (folate) deficiency
Required for single carbon metabolism
Deficiency leads to megaloblastic anemia / spina bifida
Vitamin B2 (riboflavin) deficiency
Essential component of FAD+/FADH2
Therefore cant make ATP without it
Leads to:
Cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth)
Corneal vascularization
Vitamin B3 (niacin) deficiency
Component of NAD+ / NADH
Therefore cant make ATP without it
Leads to:
Pellagra i.e. inflamed skin, diarrhoea, dementia, mouth sores
Can lead to death due to these many pathologies
Vitamin C (Ascorbic acid) deficiency
Maintains integrity of connective tissue
Antioxidant - preventing free radicals and therefore DNA damage
Inhibits laying down of cholesterol
Therefore deficiency leads to:
Scurvy
Cancer
Hypercholesterolaemia
Vitamin A (retinol) deficiency
Important in maintaining immune function and vision
Deficiency can lead to night blindness and hyperkeratosis
But excessive intake can lead to carotenodermia
Vitamin D (cholecalciferol) deficiency
Maintains serum calcium levels
Therefore bone density
Deficiency can lead to rickets
Vitamin K (phylloquinones, menaquinones) deficiency
Bleeding disorders due to its role in promoting the maturation of clotting factors
Absorption of fat soluble vitamins
Consumed and absorbed with all the other lipid components of the diet
But cant be digested by lipases
Dependent on bile salts however
Absorbed first in to the lymph and then in to the blood. Protein digestion helps release the vitamins from meat
Problems with absorption of fat soluble vitamins
Deficiencies occur due to general problems affecting fat absorption e.g. liver problems / pancreatic insufficiency
But deficiencies take a long time to manifest as the liver has a high store of these vitamins
Absorption of Vitamin A
Fat soluble vitamin
Retinol is the active form
Provitamin As are those converted in to retinol once consumed
We also have non-provitamin As which are not converted to retinol e.g. carotenoids, because they have their own important role
Each type of vitamin A has a different receptor
But are all converted in to vitamin A esters when absorbed
They are then packaged in to chylomicrons and transported via the lymphatic system. In the enterocytes Retinal enters the cells through Retinol Putative specific transporters.
Absorption of vitamin C
Ascorbate is the main form of vitamin C
It is reversibly oxidised in to an ascorbyl radical and then to a dehydroascorbate (DHA)
SVCT1 and SVCT2 are sodium dependent transporters which transport ascorbate in to cells
DHA is transported using GLUT1/3/4
Then converted to ascorbate
Not clear how ascorbate exits the intestinal cells after uptake, may involve volume sensitive anion channels (VSAC)
Absorption of vitamin B9 (folate)- long
Medicinal form of folate = PteGlu1
Can be absorbed directly
Dietary form = PteGlu7
Must be converted to PteGlu1.
Gamma-glutamyl hydrolyse converts this in the brush border cells.
The PteGlu1 is then absorbed passively in the gut/or through PCFT in the small intestine
Some folate may be absorbed later in the intestine by the Reduced Folate Carrier (RFC), an anion antiporter exchanging folate with phosphate (PO4- 3).
It is then pumped to the portal system via multi drug resistance protein 3 (MRP3)
Here it is converted to THF
How are carotenoids absorbed from mixed micelles
Through apical membrane transporters; SR-B1, (Scavenging Receptor B1), CD36 (aka FAT/FAT32).
Where is SCVT1 found
Transporter of ascorbate (vitamin C)
Found mostly in epithelial tissues (e.g., small intestine and proximal tubule of the nephron), where the transport of ascorbate is greater than that required by the cells.
Where is SCVT2 found
Transporter of ascorbate (vitamin C)
Found mainly in the brain, skeletal muscle, placenta, and eye. The transport mediated by these glycoproteins is a secondary active, saturable Na+-dependent transport
Why do we need folate
For DNA and RNA production
How the developing foetus absorbs folate
Instead of THF, N5-methyl-THF is the preferred form to be absorbed by epithelial cells. Folate receptor alpha is the main transporter along with RFC. It is transported across the endosomal membrane by PCFT and RFC. The folate is then transported to other cells by RFC. In the placenta, the maternal circulating folate is absorbed by FRα and exported into the fetal circulatory system by RFC.
Absorption of Vitamin B9 small
Some folate is produced by gut microflora
Active form is tetrahydrofolic acid (THF)
Folate is reduced in a 2 stage process to end up with this. NADPH reduces folate twice, rate limiting step. Methotrexate inhibits the reaction
Alcohol and folate
Alcohol will down-regulate expression of both PCFT and RFC reducing the ability of the placenta to transport folate. In pregnancy alcohol reduces folate levels in the foetus. Results in foetal alcohol syndrome.
Vitamin B12 deficiency- conversion of homocysteine to methionine
- There is a build up of homocysteine (Hyperhomocysteinemia or HHcy)
- Reducing NO bioavailability
- Resulting in increased endothelial dysfunction and increased oxidation of LDLs and production of clotting factors
- Therefore more likely to get atheromatous plaque and CVD
Vitamin B12 deficiency- isomerisation of Methymalonul-CoA to succinyl-CoA
- Without this it cant enter the Krebs cycle and be converted to succinyl-CoA
- Branched fatty acids accumulate
- These get incorporated in to membranes and leads to CNS damage
Vitamin B12 deficiency- Pernicious anaemia
Deficiency can come from intrinsic factor production failure/dysfunction of parietal cells/pancreatic enzyme dysfunction.
Vitamin B12 absorption
- When meat containing vitamin B12 is ingested it is subjected to digestion by pepsin and the acid in the stomach releases B12
- Haptocorrin binds to free B12 to protect it from the stomach acid. Haptocorrin is secreted by the salivary glands
- Moves to the SI as a complex, it is then neutralised by bicarbonate
- Pancreatic proteases cleave the haptocorrin from the B12 and B12 is released
- Intrinsic factors are secreted by gastric parietal cells
- B12 can then bind to intrinsic factor (IF:B12 complex).
- This complex is taken up by the CUBAM receptor in the terminal ileum
- Inside the enterocytes B12 is released from the intrinsic factor, upon acidification of the endosome and released in to the serum
- Transcobalamin-II binds to B12 in the serum and transports it through the portal system.
The folate trap
B12 can also cause B9 deficiencies.
• S-adenosyl-methionine (SAM) is converted to homocysteine.
• Methionine synthase uses a B12 dependent enzyme that uses N5-methyl-THF as a methyl donor.
• THF and Methionine are created.
• As a result B9 is not regenerated in sufficient quantities to keep up with demand.
