Regulation of Cholesterol Synthesis
The regulation cholesterol synthesis occurs at the level of liver 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). The amount of cholesterol that is synthesized in the liver is tightly regulated by dietary cholesterol levels. When dietary intake of cholesterol is high, synthesis is decreased and when dietary intake is low, synthesis is increased. However, cholesterol produced in other tissues is under no such feedback control. Cholesterol and similar sterols (bile acids, bile salts) act as regulatory molecules to maintain healthy levels of cholesterol.
- The conversion of HMG-CoA to mevalonate by HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis and is under strict regulatory control.
- HMG-CoA reductase is a transmembrane glycoprotein, located on the endoplasmic reticulum.
- This enzyme catalyzes the four-electron reduction of HMG-CoA to coenzyme A and mevalonate, which is the rate-limiting step in sterol biosynthesis.
- The activity of HMG-CoA reductase is controlled through synthesis, degradation, and phosphorylation in order to maintain the concentration of mevalonate derived products.
- In addition to the physiological regulation of HMG-CoA reductase, the human enzyme has been targeted successfully by drugs (competitive inhibitors) in the clinical treatment of high serum cholesterol levels.
Controlling serum cholesterol levels has an important therapeutic role as hypercholesterolemia often leads to the development of atherosclerosis and consequently to cardiovascular pathologies, which might result in myocardial infarction or stroke.
Recent evidence suggests that a disturbance of cholesterol homeostasis contributes to the development of a chronic inflammatory state.
Regulation of HMG-CoA reductase activity
A. Gene transcription and new protein synthesis
The primary regulatory mechanism for HMG-CoA reductase activity is feedback control of the protein levels of this enzyme.
- Cholesterol controls the expression of the HMG-reductase gene, which contains a specific DNA recognition sequence called a sterol regulatory element (SRE) (see figure on the left).
- Transcription of this gene is activated by SRE binding to a specific protein called sterol regulatory binding protein (SREBP).
- When cholesterol levels are high, SREBP resides in the endoplasmic reticulum as an inactive complex with another protein (SCAP) and cholesterol. Transcription of the HMG-CoA reductase gene does not occur.
- When cholesterol levels in the endoplasmic reticulum are low, SREBP free of cholesterol translocates to the Golgi apparatus where it is cleaved by two proteases releasing the active fragment (DNA binding domain), which translocates to the nucleus and activates transcription of the HMG-CoA reductase gene.
- Increased amounts of the enzyme increase synthesis of cholesterol.
B. Protein (enzyme) degradation by proteolysis
- HMG-CoA reductase contains sterol-sensing element (see figure on the left).
- Binding of cholesterol or bile salts to this element renders the enzyme more susceptible to proteolytic degradation. Therefore, high levels of cholesterol increase HMG-CoA reductase degradation and decrease cholesterol synthesis.
- Low levels of cholesterol are associated with decreased degradation of HMG-CoA reductase and cholesterol synthesis increases.
C. Phosphorylation
HMG-CoA exists in more active and less active form.
- Phosphorylation of HMG-CoA reductase reduces its catalytic activity (see figure on the left).
- Phosphorylation of HMG-CoA reductase at serine 871 is catalayzed by AMP-activated protein kinase (AMPK). AMPK is activated when the cellular levels of ATP fall and AMP levels increase. Thus, phosphorylation of HMG-CoA reductase by AMPK decreases the synthesis of cholesterol when energy status of the cell is low.
- Phosphorylation increases degradation of HMG-CoA reductase by increasing its susceptibility to proteolytic cleavage.
- Dephosphorylation of HMG-CoA reductase increases its activity.
- Dephosphorylation is catalyzed by HMG-CoA reductase phosphatase.
D. Competitve inhibition
HMG-CoA reductase is a subject to competitive inhibition.
- The active site of this enzyme normally accommodates NADPH (coenzyme) and the pantothenate portion of CoA.
- Statins do not compete with NADPH binding. However, the enzyme is very flexible (induced fit model) and alters its conformation to accommodate large hydrophobic groups of statins.
- Statins have a high degree of complementarity with the active site of HMG-CoA reductase and bind extremely tightly to the enzyme. In fact, statins bind with higher affinity to the enzyme ((Km in the nanomolar range) than the substrate, HMG-CoA (Km of ~ 4μM).
- Statins have an additional effect. Initial decreased levels of cholesterol induces LDL receptor synthesis, which leads to the increased removal of LDL and LDL from the blood to the peripheral tissues, thus decreasing blood LDL-cholesterol levels.
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