Statins are a widely prescribed family of drugs that lower levels of LDL by blocking synthesis of the cholesterol precursor mevalonate. In addition, these drugs have several other effects that are also potentially antiatherogenic, notably an increase in levels of HDL and its associated apolipoprotein A-I (apoA-I). Martin et al. have investigated the basis of this induction, which they show occurs as a consequence of apoA-I promoter activation in cells depleted of mevalonate. In the course of this work they have uncovered an unsuspected link between the transcription factor PPARa, which activates apoA-I expression, and the transcriptional response to statins. As the authors note, mevalonate is not only required as a precursor to cholesterol and related sterols but is also essential to maintain levels of nonsterol lipids, which have important structural and regulatory functions. In particular, they are required for the lipid modification (geranylgeranylation) of the Rho family of protein kinases. Martin et al. define the outlines of a pathway whereby geranylgeranylated RhoA suppresses PPARa activity. By blocking mevalonate synthesis, statins apparently derepress PPARa and thereby activate apoA-I transcription and the biosynthesis of HDL. This work defines a second branch of the pathway by which statins regulate the profile of lipoproteins in the blood. The first, now-classical branch involves sterol lipids and blocks LDL synthesis. The second involves the nonsterol products of mevalonate and PPARa and induces HDL synthesis. Filling in the details of the second branch may identify novel players that could be targeted specifically to increase reverse transport of cholesterol for therapeutic benefit.

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Contact: John Ashkenas
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416-946-7593
Journal of Clinical Investigation
29-May-2001