Blood Lipids and Lipoproteins Flashcards
What is the structure of cholesterol?
4-ring structure with 27 carbons
What are the sources of cholesterol?
- Exogenous (diet)- 1g/day
2. Endogenous (synthesised in liver, intestines, adrenal glands and reproductive tissues)- 0.5-1g/day
What are the steps in the synthesis of Cholesterol?
- Synthesis of Isopentenyl Pyrophosphate
- Formation of Squalene from 6 Isopentenyl Pyrophosphate
- Cyclisation of Squalene to form Cholesterol
What happens during the synthesis of Isopentenyl Pyrophosphate?
- Acetoacyl CoA + Acetyl CoA–> HMG-CoA
- HMG CoA–> Mevalonate
- Mevalonate–>–>–>–> Isopentenyl Pyrophosphate
How is HMG-CoA converted to Mevalonate?
It is reduced by HMG-CoA Reductase
How is Mevalonate converted to Isopentenyl Pyrophosphate?
It undergoes phosphorylation reaction:
1. Mevalonate–> 5-Phospho Mevalonate–> 5-Pyrophospho Mevavlnate–> Isopentenyl Pyrophosphate
What happens in the formation of Squalene from 6 Ispoentenyl Pyrophosphate?
The 6 Isopentenyl Pyrophosphate molecules are joined together via condensation reactions
What happens in the cyclisation of Squalene to form cholesterol?
- Squalene is oxidised to Squalene 2,3-Epoxide
- Squalene 2,3-epoxide is cyclised to Lanosterol
- Lanosterol loses 3 Methyl Groups and 1 double bond, and 1 double bond is shifted to make cholesterol
How is the synthesis of Cholesterol regulated in the body?
Controlled by negative feedback mechanism mediated primarily by changes in the amount/activity of HMG-CoA Reductase
How is the amount/activity of HMG-CoA Reductase controlled in the body?
- Control of the Rate of Synthesis of Reductase mRNA
- Control of the Rate of translation of reductase mRNA
- Degradation of the Reductase
- Phosphorylation of the Reductase
How is the rate of synthesis of HMG CoA reductase mRNA controlled?
When Cholesterol levels are low, Sterol Regulatory Element Binding Protein (SREBP) binds to the Endoplasmic Reticulum and promotes transcription of HMG-CoA Reductase mRNA
How is the rate of translation of HMG CoA reductase mRNA controlled?
It is inhibited by non-sterol metabolites derived from mevalonate and dietary cholesterol–> Negative feedback from production of cholesterol
When does degradation of the HMG CoA Reductase occur?
When there is too much cholesterol, the enzyme can mark itself for ubiquitination/proteolysis (suicide)
What does phosphorylation do to HMG CoA Reductase?
Decrease the activity of the reductase in response to low levels of ATP
How is cholesterol transported in the body?
Transported in the form of lipoproteins–> VLDL, LDL, HFL
How is Cholesterol Pharmacologically regulated?
- Statins inhibit HMG-CoA Reductase
- Sequestering Bile Acids in the Intestine–> Cholestramine and Coletipol reduce absorbance of exogenous cholesterol
- Altering the relative levels of different lipoproteins–> Decrease amounts of VLDL and LDL
What are the derivatives of Cholesterol?
- Bile Salts
- Steroid Hormones
- Vitamin D
What is the function of Bile Acids and Bile Salts?
Elimination of Cholesterol from the body by conversion of Cholesterol into Bile Acids and Bile Salts which can be excreted
How are Bile Acids and Bile Salts made from Cholesterol?
Cholesterol is hydroxylised by 7a-hydroxylase to from 7a-hydroxycholesterols Cholic acid or Chenodeoxycholic Acid (Bile Acids). Bile Acids are combined with either Glycine or Taurine in the Liver to form Bile SaltsE.g. Glycocholic Acid
What happens when Bile Salts are exposed to bacterial flora of the intestine?
- Generation of bile acids by removal of the glycine or taurine
- Production of secondary bile salts by the removal of an -OH group
Where are Bile Salts Synthesised?
Liver
Where are Bile Salts stored?
Gall Bladder
Where are Bile Salts released?
Small Intestine
What is Cholesterol Gall-Stone Disease?
There is not enough bile salts being secreted to handle the amount of cholesterol being secreted–> so the cholesterol precipitates in the gall bladder
