The role of HMGCR alternative splicing in statin efficacy

Abstract

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, are widely prescribed to lower plasma cholesterol levels and reduce cardiovascular disease risk. Despite the well-documented efficacy of statins, there is large interindividual variation in response. Using a panel of immortalized lymphocyte cell lines incubated with simvastatin, we recently found that the magnitude of expression of an alternatively spliced HMGCR transcript lacking exon 13 was inversely correlated with in vivo reductions of total cholesterol, low-density lipoprotein cholesterol, apoB, and triglycerides after statin treatment of the individuals from whom the cells were derived. This review will discuss the potential significance of alternative splicing as a mechanism contributing to variation in statin efficacy as well as the use of immortalized lymphocyte cell lines for identifying pharmacogenetically relevant polymorphisms and molecular mechanisms.

Figure 1

Scheme of HMGCR alternative splicing

Figure 2

Oligomerization of HMGCR catalytic domains. The catalytic domain of the classical HMGCR enzyme, HMGCR13(+), has been shown to exist as a tetramer comprised of two dimers (Istvan et al. 2000). This conformation is fully active and sensitive to competition inhibition by statins. Although evidence suggests that deletion of exon 13 abolishes HMGCR enzymatic activity (Burkhardt et al. 2008), these studies did not consider the possibility that the 13(+) and 13(−) monomers may form heterogenous dimers or tetramers comprised of varying compositions of the 13(+) and 13(−) monomers. In the context of these hypothetical conformations, 13(−) may attenuate HMGCR enzyme activity and statin sensitivity, consistent with our reports that modulating the relative levels of the 13(+) to 13(−) transcript alters the statin sensitivity of the resulting HMGCR enzyme.