title: Systematic investigation of cellular response and pleiotropic effects in atorvastatin-treated liver cells by MS-based proteomics.
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.
authors: School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology , Atlanta, Georgia 30332, United States.
authors: Haopeng
authors: H
authors: Xiao
authors: Weixuan
authors: W
authors: Chen
authors: George X
authors: GX
authors: Tang
authors: Johanna M
authors: JM
authors: Smeekens
authors: Ronghu
authors: R
authors: Wu
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D013058:Mass Spectrometry; D040901:Proteomics
chemical_list: D000924:Anticholesteremic Agents; D000069059:Atorvastatin
keywords: HepG2 cells; LC−MS; atorvastatin; global and quantitative analysis of proteins and protein phosphorylation; liver cell response to statin; pleiotropic effects