1. Statins Molecular mechanisms of action SREBP feedback control
Figure 99 Statins inhibit HMG-CoA reductase and block the cholesterol synthesis pathway. Decreased cellular cholesterol production induces activation of sterol regulatory element binding protein (SREBP), a transcription factor, particularly in hepatocytes. SREBP activation induces increased LDL receptor production and thus increased clearance of LDL from the blood.

2. SREBP* regulates the LDL receptor Three-step activation process
Figure 100 Sterol regulatory element binding protein is usually located on the endoplasmic reticulum (ER). Low levels of intracellular cholesterol induce cleavage of SREBP at two points on the molecule. This gives rise to the active form of SREBP, which detaches from the ER and migrates to the nucleus, where it activates LDL receptor gene expression.

3. Common properties of PPARa activators and statins Parietal vascular effects
Figure 101 Statins also have similar effects to fibrates in relation to endothelial dysfunction, thrombogenicity and vascular inflammation.

4. Statins and PPARa activators, similar effects Similar effector, PPARa?
Figure 102 It has been demonstrated that statins indirectly activate PPARa, which could explain why statins and PPARa activators have the same properties.

5. Statins induce PPARa activity
Figure 103 Inhibition of HMG-CoA reductase results in decreased levels of mevalonate (an intermediary in the synthesis of cholesterol). Mevalonate induces production of geranylgeranyl pyrophosphate and geranylated proteins (like Rho) which pass into the nucleus and phosphorylate PPARa. Lower levels of mevalonate result in reduced phosphorylation of PPARa, thus rendering it more responsive to activation in the presence of naturally-occurring PPARa activators (e.g. fatty acid derivatives).

6. Human apo A-I mRNA is induced by statins in a dose-dependent manner
Figure 104 In common with fibrates, statins increase apo A-I expression in hepatocytes and therefore increase HDL. This effect is dose dependent, but clinically to a lesser extent.

7. Statins act on apo A-I mRNA expression at the transcriptional level Inhibition by actinomycin D
Figure 105 Actinomycin D blocks the increased synthesis of apo A-I by statins. This indicates that the site of statin action is at the level of transcription.