Dataset Information

Effect of Rosuvastatin on the Lipoprotein Proteome

ABSTRACT: Statins lower plasma cholesterol by as much as 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all are related to LDL-C lowering. We performed a small clinical pilot study to assess the impact of statins on lipoprotein-associated proteins in healthy individuals (n=10) with normal LDL-C (<130 mg/dL), who were treated with rosuvastatin (20 mg/day) for 28 days. Proteomic analysis of size-exclusion chromatography isolated LDL, HDL-L (large) and HDL-S (small) fractions and spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool and included both increases and decreases in several proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the rosuvastatin treatment was an increase in alpha-1-antirypsin (A1AT) spectral counts associated with HDL-L particles. Quantitative measurement by ELISA confirmed an average 5.7-fold increase in HDL-L associated A1AT. Molecular modeling predictions indicated that the hydrophobic reactive center loop of A1AT, the functional domain responsible for its protease inhibitor activity, is likely involved in its lipid binding and its association with HDL was found to protect A1AT against oxidative inactivation. Cell culture experiments, using J774 macrophages, demonstrated that the association of A1AT with HDL enhances its anti-protease activity, preventing elastase induced production of tumor necrosis factor alpha. In conclusion, we show that statins can significantly alter the protein composition of both LDL and HDL and our studies reveal a novel functional relationship between A1AT and HDL. The upregulation of A1AT on HDL enhances its anti-inflammatory functionality, which may contribute to the non-lipid lowering beneficial effects of statins.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

SUBMITTER: Scott Gordon

LAB HEAD: Scott M. Gordon

PROVIDER: PXD002633 | Pride | 2018-10-24

REPOSITORIES: Pride

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Publications

Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties.

Gordon Scott M SM McKenzie Benjamin B Kemeh Georgina G Sampson Maureen M Perl Shira S Young Neal S NS Fessler Michael B MB Remaley Alan T AT

Molecular & cellular proteomics : MCP 20151019 12

Statins lower plasma cholesterol by as much as 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all are related to low density lipoprotein cholesterol (LDL-C) lowering. We performed a small clinical pilot study to assess the impact of statins on lipoprotein-associated proteins in healthy individuals (n = 10) with normal LDL-C (<130 mg/dL), who were treated with rosuvastatin (20 mg/day) for 28 days. Proteomic analysis of size-exclu ...[more]

PMID: 26483418

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Project description:In previous in vitro study, we reported potential mechanism of cholesterol-lowering effect of Lactobacillus brevis119-2 (119-2) isolated from turnip M-bM-^@M-^\Tsuda kabuM-bM-^@M-^] is due to incorporation of cholesterol into 119-2 cell. In this study, we analyzed serum cholesterol and hepatic gene expression of Sprague-Dawley (SD) rat fed diet containing cholesterol with or without 119-2 for 2 weeks, to evaluate the cholesterol-lowering effect of 119-2 in vivo. Serum cholesterol of SD rat fed diet with 119-2 significantly decreased compared to SD rat fed diet without 119-2, and both viable and dead 119-2 indicated the effect. The result of hepatic gene analysis using DNA microarray suggested that potential mechanism of the cholesterol-lowering effect of 119-2 in vivo is inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA reductase by Insig (insulin induced gene) that is endoplasmic reticulum membrane protein, and catabolizing cholesterol to bile acid by Cyp7a1 (cytochrome P450 a1) that is the rate-limiting enzyme in the synthesis of bile acid from cholesterol. In addition, we concluded feeding 119-2 decreased serum low density lipoprotein (LDL) cholesterol by overexpression of Ldlr (LDL receptor gene). On the other hand, feeding Lactobacillus acidophilus ATCC43121 (ATCC) increased high density lipoprotein (HDL) cholesterol by over expression of Abca1 (ATP binding cassette sub-family A member 1 gene) and Angplt3 (Angiopoietin-like 3). These results suggested that 119-2 decrease the risk of atherosclerosis by serum cholesterol-lowering effect and improving effect of fatty liver and the LH (LDL cholesterol / HDL cholesterol) ratio. Lactobacillus brevis119-2 (119-2) was isolated from turnip M-bM-^@M-^\Tsuda kabuM-bM-^@M-^] harvested in Matsue city, Shimane Prefecture, Japan, and was stored at Shimane Institute for industrial Technology. Male Jcl: SD rat (4 weeks of age) were obtained from CLEA Japan, Inc. (Tokyo, Japan). Rats were maintained under controlled environmental conditions (temperature 23 M-BM-1 3 M-KM-^ZC, relative humidity 55% M-BM-1 25%, 12/12hr light - dark cycle) and given food and water ad libitum. All rats were acclimated 1 week prior to the experiment. Two groups of 11 rats each were treated respective group diets for 2weeks. Control group was fed high-cholesterol diet containing 10 g cholesterol/kg, 5 g cholic acid/kg, 985 g mouse & rat & rabbit diet (CRF-1) /kg obtained from Oriental yeast Co., Ltd (Tokyo, Japan). The other group was fed same highcholesterol diet with 10 g freeze-dried viable 119-2 /kg. This study and all procedures were approved by regulations and code of ethics in experimental animals Chitose Japan Food Research Laboratories.

Dataset Information

Effect of Rosuvastatin on the Lipoprotein Proteome

Publications

Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties.

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