Case 12- vitamin absorption

Question 1

Re-esterification

Answer 1

Only done to long-chain FAs (12C+) and the 2MG obtained from TAGS

Question 2

Re-esterification of TAG

Answer 2

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)

Question 3

Re-esterification of Cholesterol

Answer 3

1 ATP is consumed
• Cholesterol + FA-CoA → Acyl-Cholesterol + CoA
By the enzyme Acyl-CoA cholesterol acyltransferase (ACAT)

Question 4

Synthesis of lipids

Answer 4

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).

Question 5

Where are lipids secreted into

Answer 5

The apolipoprotein called Chylomicrons are secreted into the lymphatic system. TAG and cholesterol from the diet bypass the liver.

Question 6

Clinical significance of lipid metabolism

Answer 6

• 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.

Question 7

Passive uptake of fats

Answer 7

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

Question 8

Active uptake of fats

Answer 8

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

Question 9

Drugs that affect lipid absorption- Orlistat

Answer 9

• inhibits gastric and pancreatic lipases

- fats can no longer be absorbed

Question 10

Drugs that affect lipid absorption- Ezetimibe

Answer 10

• blocks NPC1L1 so inhibits cholesterol absorption

Question 11

Vitamins

Answer 11

Are used as co-enzymes. They are essential apart from vitamin D which we make ourselfs

Question 12

Classification of vitamins

Answer 12

Water soluble (C,B) or fat soluble (A, D, K, E)

Question 13

B-complex vitamins

Answer 13

Water soluble vitamins
Vitamins involved in energy production / haematopoesis
Include C/B1/B2/B3/B12/folic acid etc

Question 14

Vitamin B1 (thiamine) deficiency

Answer 14

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

Question 15

Vitamin B9 (folate) deficiency

Answer 15

Required for single carbon metabolism

Deficiency leads to megaloblastic anemia / spina bifida

Question 16

Vitamin B2 (riboflavin) deficiency

Answer 16

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

Question 17

Vitamin B3 (niacin) deficiency

Answer 17

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

Question 18

Vitamin C (Ascorbic acid) deficiency

Answer 18

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

Question 19

Vitamin A (retinol) deficiency

Answer 19

Important in maintaining immune function and vision

Deficiency can lead to night blindness and hyperkeratosis
But excessive intake can lead to carotenodermia

Question 20

Vitamin D (cholecalciferol) deficiency

Answer 20

Maintains serum calcium levels
Therefore bone density

Deficiency can lead to rickets

Question 21

Vitamin K (phylloquinones, menaquinones) deficiency

Answer 21

Bleeding disorders due to its role in promoting the maturation of clotting factors

Question 22

Absorption of fat soluble vitamins

Answer 22

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

Question 23

Problems with absorption of fat soluble vitamins

Answer 23

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

Question 24

Absorption of Vitamin A

Answer 24

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.

Question 25

Absorption of vitamin C

Answer 25

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)

Question 26

Absorption of vitamin B9 (folate)- long

Answer 26

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

Question 27

How are carotenoids absorbed from mixed micelles

Answer 27

Through apical membrane transporters; SR-B1, (Scavenging Receptor B1), CD36 (aka FAT/FAT32).

Question 28

Where is SCVT1 found

Answer 28

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.

Question 29

Where is SCVT2 found

Answer 29

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

Question 30

Why do we need folate

Answer 30

For DNA and RNA production

Question 31

How the developing foetus absorbs folate

Answer 31

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.

Question 32

Absorption of Vitamin B9 small

Answer 32

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

Question 33

Alcohol and folate

Answer 33

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.

Question 34

Vitamin B12 deficiency- conversion of homocysteine to methionine

Answer 34

• 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

Question 35

Vitamin B12 deficiency- isomerisation of Methymalonul-CoA to succinyl-CoA

Answer 35

• 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

Question 36

Vitamin B12 deficiency- Pernicious anaemia

Answer 36

Deficiency can come from intrinsic factor production failure/dysfunction of parietal cells/pancreatic enzyme dysfunction.

Question 37

Vitamin B12 absorption

Answer 37

• 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.

Question 38

The folate trap

Answer 38

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.