Dataset Information

Protein markers of dysfunctional HDL in scavenger receptor class B type I deficient mice.

ABSTRACT:

Background

Scavenger receptor class B type I (SR-BI) plays a key role in high density lipoproteins (HDL) metabolism. SR-BI deficiency in mice results in enhanced susceptibility to atherosclerosis with abnormal large, cholesterol enriched, and functional impaired HDL. This study was to characterize the protein markers of dysfunctional HDL in SR-BI deficient (SR-BI^-/-) mice and to test if the defective of HDL might be affected by probucol treatment.

Methods

Shotgun proteomics and 2-D gel electrophoresis were performed to examine the profile of HDL protein and distribution of HDL particles isolated from SR-BI^-/- mice. HDL's cell-function, paraoxonase 1 (PON1) and myeloperoxidase activity were assessed. The mice were treated with 1.2 mg/g/day probucol for 6 weeks and the impact on HDL protein markers was analyzed. The differential proteins were quantified by Western blotting.

Results

The relative amount of protein in SR-BI^-/- HDL was decreased by about 25% compared to that in HDL from wild type (WT) mice. Compared to WT HDL, relative protein abundance of representative apoAI and PON1 in SR-BI^-/- HDL were significantly reduced, whereas acute-phase protein serum amyloid A (SAA) and apoAIV, proteinase inhibitor proteins ?-1-antitrypsin (A1AT) were increased. The distribution of plasma apoAI-containing HDL particles in SR-BI^-/- mice was also dramatically altered, although plasma apoAI level was no difference. The protein alterations were accompanied with dysfunction of SR-BI^-/- HDL, evidenced by impaired cholesterol homeostasis in macrophages, and reduced anti-oxidative and anti-inflammatory effects. Probucol treatment of SR-BI^-/- mice could restored the relative contents of critical proteins including apoAI, PON1, SAA, apoAIV and A1AT on HDL, and improve HDL dysfunction despite decreased HDL-C level.

Conclusion

SR-BI deficiency leading to dysfunctional HDL is closely related to alteration of HDL protein, suggesting that identification of apoAI, PON1, SAA, apoAIV, and A1AT may serve as the valuable protein markers for diagnosis and therapeutics of dysfunctional HDL-related metabolic diseases.

SUBMITTER: Cao J

PROVIDER: S-EPMC5992774 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Protein markers of dysfunctional HDL in scavenger receptor class B type I deficient mice.

Cao Jia J Xu Yanyong Y Li Feifei F Shang Liang L Fan Daping D Yu Hong H

Journal of translational medicine 20180607 1

<h4>Background</h4>Scavenger receptor class B type I (SR-BI) plays a key role in high density lipoproteins (HDL) metabolism. SR-BI deficiency in mice results in enhanced susceptibility to atherosclerosis with abnormal large, cholesterol enriched, and functional impaired HDL. This study was to characterize the protein markers of dysfunctional HDL in SR-BI deficient (SR-BI<sup>-/-</sup>) mice and to test if the defective of HDL might be affected by probucol treatment.<h4>Methods</h4>Shotgun proteo ...[more]

PMID: 29879989

Similar Datasets

Project description:BackgroundHigh-density lipoprotein (HDL) plays an antiatherogenic role by mediating reverse cholesterol transport (RCT), antioxidation, anti-inflammation, and endothelial cell protection. Recently, series of evidence have shown that HDL can also convert to proatherogenic HDL under certain circumstances. Plasma paraoxonase 1 (PON1) as an HDL-bound esterase, is responsible for most of the antioxidant properties of HDL. However, whether PON1 can serve as a therapeutic target of dysfunctional HDL-related atherosclerosis remains unclear.MethodsIn this study, scavenger receptor class B type I deficient (Scarb1-/- ) mice were used as the animal model with dysfunctional HDL and increased atherosclerotic susceptibility. Hepatic PON1 overexpression and secretion into circulation were achieved by lentivirus injection through the tail vein. We monitored plasma lipids levels and lipoprotein profiles in Scarb1-/- mice, and measured the levels and activities of proteins associated with HDL function. Meanwhile, lipid deposition in the liver and atherosclerotic lesions was quantified. Hepatic genes relevant to HDL metabolism and inflammation were analyzed.ResultsThe results showed the relative levels of PON1 in liver and plasma were increased by 1.1-fold and 1.6-fold, respectively, and mean plasma PON1 activity was increased by 63%. High-level PON1 increased the antioxidative and anti-inﬂammatory properties, promoted HDL maturation and macrophage cholesterol efflux through increasing HDL functional proteins components apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and lecithin-cholesterol acyltransferase (LCAT), while decreased inflammatory protein markers, such as serum amyloid A (SAA), apolipoprotein A4 (APOA4) and alpha 1 antitrypsin (A1AT). Furthermore, hepatic PON1 overexpression linked the effects of antioxidation and anti-inflammation with HDL metabolism regulation mainly through up-regulating liver X receptor alpha (LXRα) and its downstream genes. The pleiotropic effects involved promoting HDL biogenesis by raising the level of APOA1, increasing cholesterol uptake by the liver through the APOE-low density lipoprotein receptor (LDLR) pathway, and increasing cholesterol excretion into the bile, thereby reducing hepatic steatosis and aorta atherosclerosis in Western diet-fed mice.ConclusionsOur study reveals that high-level PON1 improved dysfunctional HDL and alleviated the development of atherosclerosis in Scarb1-/- mice. It is suggested that PON1 represents a promising target of HDL-based therapeutic strategy for HDL-related atherosclerotic cardiovascular disease.

Dataset Information

Protein markers of dysfunctional HDL in scavenger receptor class B type I deficient mice.

Background

Methods

Results

Conclusion

Publications

Protein markers of dysfunctional HDL in scavenger receptor class B type I deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets