Regulation of Biosynthesis of Cholesterol


(Answer to Biochemistry Question LM-02   )

 

Cholesterol is very important in the constitution of membranes, not only because of its structural rol but also because of its influence in membrane fluidity. Cholesterol is also very important as precursor of steroid hormones, like the suprarenal cortex hormones glucocorticoids and mineralocorticoids, and sex hormones and progesterone. Vitamin D and bile salts are also important cholesterol derivatives. Besides, if we consider the relationship between blood levels of cholesterol and cardiovascular diseases, it is not difficult to understand that cholesterol biosynthesis is very regulated by different mechanisms.

 

It has been posted before that  the enzyme HidroxyMethylGlutaryl CoA reductase (HMGCoA reductase) is the key enzyme in the regulation of Cholesterol Synthesis. The main mechanisms of control that affect this enzyme appears in the following table:

 

 

Molecular Mechanism

Specifications:

Allosterism

Cholesterol and unsaturated fatty acids are allosteric inhibitors of this enzyme.

Covalent Modification

Phosphorylation of the enzyme inactivates it. This phosphorylation is triggered by glucagon through the kinases system.

Dephosphorylation, triggered by insulin through the activity of phosphatases, activates the enzyme.

Genetic Regulation

Cholesterol content inside the cell regulates the synthesis of the enzyme at a transcriptional level.

 

Besides being the key enzyme in the physiological control of cholesterol synthesis, the HMGCoA reductase is also a key enzyme in the pharmacological control of the synthesis: statin drugs, like Atorvastatin (Lipitor), Sinvastatin (Zocor), Lovastatin (Mevacor), Pravastatin (Pravachol) and others, act inhibiting the action of this enzyme, and provoking consequently a decrease of the synthesis of cholesterol. This decrease in the intracellular synthesis of cholesterol triggers a mechanism of increasing the cellular uptake of plasmatic cholesterol, decreasing cholesterol concentration in blood.

 

(The mechanisms that integrate the synthesis of cholesterol  and the level of plasmatic cholesterol will be considered in detail in a future post, when metabolism of lipoproteins will be discussed).

 

More information about the Regulation of the synthesis of Cholesterol can be found at:

 

http://www.med.unibs.it/~marchesi/cholest.html#regulation

 

http://themedicalbiochemistrypage.org/cholesterol.html#regulation

 

 

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