Systematic Investigation of
Cellular Response and
Pleiotropic Effects in Atorvastatin-Treated Liver Cells by MS-Based
Proteomics
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Abstract
For
decades, statins have been widely used to lower cholesterol
levels by inhibiting the enzyme HMG Co-A reductase (HMGCR). It is
well-known that statins have pleiotropic effects including improving
endothelial function and inhibiting vascular inflammation and oxidation.
However, the cellular responses to statins and corresponding pleiotropic
effects are largely unknown at the proteome level. Emerging mass spectrometry-based
proteomics provides a unique opportunity to systemically investigate
protein and phosphoprotein abundance changes as a result of statin
treatment. Many lipid-related protein abundances were increased in
HepG2 cells treated by atorvastatin, including HMGCR, FDFT, SQLE,
and LDLR, while the abundances of proteins involved in cellular response
to stress and apoptosis were decreased. Comprehensive analysis of
protein phosphorylation demonstrated that several basic motifs were
enriched among down-regulated phosphorylation sites, which indicates
that kinases with preference for these motifs, such as protein kinase
A and protein kinase C, have attenuated activities. Phosphopeptides
on a group of G-protein modulators were up-regulated, which strongly
suggests that cell signal rewiring was a result of the effect of protein
lipidation by the statin. This work provides a global view of liver
cell responses to atorvastatin at the proteome and phosphoproteome
levels, which provides insight into the pleiotropic effects of statins