2.5 - Cholesterol Flashcards
1
Q
Sources of fats
A
Fats are derived from three primary sources:
- the diet
- de novo biosynthesis (liver)
- storage depots in adipose
2
Q
Bile salts
A
- breakdown product of cholesterol metabolism
- bile salts are generated by the liver and stored in the gallbladder
- during digestion, they pass from the bile duct into the intestine
- emulsify fats in the intestine, aiding their digestion and absorption of fats and also that of fat-soluble vitamins
- lack of bile salts = majority of fat passing through gut undigested and unabsorbed resulting in steatorrhea (fatty stool)
3
Q
Orlistat (tetrahydrolipstatin)
A
- potent inhibitor of gastric and pancreatic lipase (so fats are excreted and less fats absorbed = weight loss)
- chemically synthesised derivative of lipstatin
- reduces fat absorption by 30%, which is almost completely excreted by the faecal route –> effective in treating obesity for up to two years
- main side effects: abdominal pain, urgency to defecate, increased flatus and steatorrhea
4
Q
Lipoproteins
A
- lipids are transported in the plasma by lipoproteins which can be characterised according to their density (in order of lowest to highest):
- chylomicrons (CM) - intestines (enterocytes) - dietary fat transport
- very low density lipoproteins (VLDL) - liver - endogenous fat transport
- intermediate density lipoproteins (IDL) - source is VLDL - LDL precursor
- low density lipoproteins (LDL) - source is IDL - cholesterol transport
- high density lipoproteins (HDL) - liver - reverse cholesterol transport
5
Q
What are chylomicrons?
A
- hydrophilic outer shell, hydrophobic core - allows transport of hydrophobic molecules in an aqueous environment
- digested dietary products are absorbed by enterocytes that line the brush border of the small intestine
- triglycerides are resynthesized (by enterocytes) under the control of several enzymes before incorporation into CMs
- these are transported via the lymphatics and on into the bloodstream
- they acquire apoproteins from HDL following release into the bloodstream
6
Q
What is lipoprotein lipase?
A
- CMs travel from the lacteals of the intestine to the thoracic duct and to the left subclavian vein where they enter the bloodstream
- lipoprotein lipase (integral membrane protein) is located on the capillary endothelial cells lining a variety of tissues including adipose, heart and skeletal muscle –> key for recognising CM and digesting contents
- once digested, fatty acids undergo B-oxidation + glycerol returns to the liver for gluconeogenesis
7
Q
Life cycle of chylomicrons
A
intestinal villus –> nascent CM –(HDL=transfer of apoproteins)–> CM (recognised by lipoprotein lipase) –> glycerol + free fatty acids (FFA) –> CM remnants –(transfer of apoproteins)–> uptake of remnants by liver –> nascent CM
8
Q
Cholesterol
A
- cholesterol is a steroid
- it increases or decreases membrane stiffness, depending on temperature and nature of membrane
- more than 90% of cholesterol in the body is found in cell membranes - brings together/apart phospholipids, changing membrane fluidity
- polar hydrophilic head group, non-polar hydrophobic hydrocarbon tail
- 4 ring structure, C27 species
9
Q
Cholesterol biosynthesis
A
- all physiological requirements for cholesterol are supplied by the liver through de novo synthesis of cholesterol from acetyl CoA
- synthesised via a pathway that can be split in three main parts:
1) synthesis of 5C isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm)
2) condensation of six molecules of isopentenyl pyrophosphate to form 30C squalene (cytoplasm)
3) cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER)
10
Q
Step 1 of cholesterol biosynthesis
A
- Condensation of 2 acetyl-CoA molecules to form acetoacetyl CoA: 2 acetyl CoA –> acetoacetyl CoA – B-ketothiolase enzyme, produces 1 CoA
- Condensation of another acetyl-CoA molecule to form HMG-CoA: acetoacetyl CoA + acetyl CoA –> 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) – HMG-CoA synthase enzyme, produces CoA from H2O
- HMG-CoA is reduced to generate mevalonate – catalysed by HMG-CoA reductase, which is under negative feedback control by the end product cholesterol, the intermediate mevalonate and bile salts (key control step, end product inhibition)
- Mevalonate undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form 3-isopentenyl pyrophosphate (activated isoprene unit)
11
Q
Step 2 of cholesterol biosynthesis
A
- via an isomerisation reaction, isopentenyl PP can produce dimethylallyl pyrophosphate
- this can condense with a unit of isopentenyl-PP to form the C10 geranyl-PP
- a third isopentenyl-PP molecule is added to form the C15 intermediate farnesyl-PP
- two farnesyl-PP molecules condense to form C30 squalene + 2 molecules of pyrophosphate
12
Q
Step 3 of cholesterol biosynthesis
A
squalene –> squalene epoxide –> protosterol cation –> lanosterol –(19 further steps producing HCOOH + 2CO2)–> cholesterol
13
Q
Steroid hormones
A
- cholesterol is the basis of steroid hormones
- the precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase
- all 5 classes of steroid hormones come from pregnenolone - progestagens, glucocorticoids, mineralocorticoids, androgens, estrogens
14
Q
Synthesis of vitamin D from cholesterol
A
7-dehydrocholesterol –(UV)–> previtamin D3 –> vitamin D3 –(hydroxylation)–> calcitriol
- most foods have a low vitamin D3 content
- exposure of skin to sunlight is required to initiate the reaction scheme
- calcitriol plays a key role in calcium metabolism
- vitamin D3 deficiency in childhood leads to rickets
15
Q
Bile salt synthesis
A
- bile salts are the major breakdown products of cholesterol
- account for half of the cholesterol made each day by the liver
- cholesterol is converted by a series of reactions into the primary bile salt glycocholate and also taurocholate
