Question

12. How is regulation of cholesterol biosynthesis achieved in cells? Identify a component of this biosynthetic pathway that would be a good pharmacological target for regulating cholesterol biosynthesis. (6pts)

Answer 1

Regulation of Cholesterol Synthesis occurs in following steps.main regulatory enzyme of the pathway is HMG coA reductase, located in endoplasmic reticulum of cell. Multiple level regulation exist in cell for regulation of cholesterol level . which are described below

1) regulation at transcription:

When sufficient cholesterol is present -  transcription of HMG CoA reductase is suppressed, and cellular synthesis of cholesterol is decreased.

When cholesterol in diet is low- , synthesis is increased

2. Cholesterol regulates the expression of HMG CoA reductase gene and LDLR (LDL receptor) gene. A specific sequence known as the sterol regulatory element (SRE) is present in DNA. SRE binding by sterol regulatory element binding protein (SREBP) is essential for the transcription of these genes.

When cholesterol levels are sufficiently high, the SREBP remains as an inactive precursor. It will not bind to SRE thus transcription of HMG ciA reductase and LDL R does not occur. And thus decrese synthesis of cholesterol and decreases uptake of cholesterol lead to decrease cholesterol level.

When cholesterol is less, - SCAP ( act as cholesterol sensor present on golgi body ) escorts SREBP to Golgi bodies. Two golgi proteases (S1P and S2P) sequentially cleave the SREBP to a protein, this binds to SRE element in DNA , which activates the transcription of HMGCoA reductase gene and increase synthesis of cholesterol in cell.

3. Covalent modification: this is kind of Short-term regulation done by covalent modification of the enzyme. Dephospho form of enzyme is active insulin promote aynthesis of cholesterol.

4. Cortisol and glucagon decrease its activity.

5.. Drugs: Lovastatin and other "statin" group of drugs are competitive inhibitors of HMG CoA reductase. So, they are used in clinical practice to reduce cholesterol level in blood.

HMG COA reductase is point where various statin drugs act .they basically act as competitive inhibitor and by inhibiting HMG COA reductase decrease cholesterol synthesis.