Systematic Investigation of Cellular Response and Pleiotropic Effects in Atorvastatin-Treated Liver Cells by MS-Based Proteomics

作者：Xiao Haopeng; Chen Weixuan; Tang George X; Smeekens Johanna M; Wu Ronghu^*

来源：Journal of Proteome Research, 2015, 14(3): 1600-1611.

DOI：10.1021/pr501277g

• liver cell response to statin
• pleiotropic effects
• HepG2 cells
• atorvastatin
• global and quantitative analysis of proteins and protein phosphorylation
• LC-MS

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.

• 出版日期2015-3