Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL

Zannis, Vassilis I.; Chroni, Angeliki; Krieger, Monty

doi:10.1007/s00109-005-0030-4

Cited by 345 publications

(319 citation statements)

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“…molecules of apoA-I (3,6,7). In this form, the conformation of apoA-I is an excellent coactivator for the plasma enzyme lecithin:cholesterol acyl transferase (LCAT) that rapidly converts apoA-I containing lipid particles to mature or spherical HDL with a core of cholesterol ester.…”

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confidence: 99%

Conformational Adaptation of Apolipoprotein A-I to Discretely Sized Phospholipid Complexes

et al. 2007

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The conformational constraints for apoA-I bound to recombinant phospholipid complexes (rHDL) were attained from a combination of chemical cross-linking and mass spectrometry. Molecular distances were then used to refine models of lipid-bound apoA-I on both 80 and 96Å diameter rHDL particles. To obtain molecular constraints on the protein bound to phospholipid complexes, three different lysine-selective homo-bifunctional cross-linkers with increasing spacer arm lengths (i.e., 7.7, 12.0, and 16.1 Å) were reacted with purified, homogeneous recombinant 1-palmitoyl-2-oleoylsn-glycerol-3-phosphocholine (POPC) apoA-I rHDL complexes of each diameter. Cross-linked dimeric apoA-I products were separated from monomeric apoprotein using 12% SDS PAGE, then subjected to in-gel trypsin digest, and identified by MS/MS sequencing. These studies aid in the refinement of our previously published molecular model of 2 apoA-I molecules bound to ~150 molecules of POPC and suggest that the protein hydrophobic interactions at the N-and C-terminal domains decrease as the number of phospholipid molecules or "lipidation state" of apoA-I increases. Thus, it appears that these incremental changes in the interaction between the N-and C-terminal ends of apoA-I stabilize its tertiary conformation in the lipid-free state as well as allowing it to unfold and sequester discrete amounts of phospholipid molecules.Apolipoprotein A-I (apoA-I) is a 28 kDa protein synthesized by the liver and intestine and is responsible for modulating the formation, metabolism, and catabolism of high density lipoprotein cholesterol. HDL has been known for decades to be a negative risk factor for predicting the development of coronary artery disease in humans, but the specific mechanism (s) responsible for its protective role in cholesterol metabolism continues to be studied and elucidated (1-3).ApoA-I shares a number of similarities to other members of the apoprotein super gene family, as well as possessing a unique set of properties related to its unique role in lipid metabolism (4). Totally soluble in aqueous solution, apoA-I monomers exist in a lipid-free state, but also avidly bind to each other, as well as lipid surfaces (5). Although apoA-I readily binds lipid surfaces, the formation of small apoA-I containing phospholipid and cholesterol particles, an important step in HDL metabolism, does not occur to a significant extent in the absence of the ABCA1 transporter. During the formation of "nascent" HDL, monomers of lipid-free apoA-I bind to ABCA1 which adds phospholipid and cholesterol to yield a particle containing two 1To whom correspondence should be addressed: Dept. of Pathology, Section on Lipid Sciences, Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-716-2147; Fax 336-716-6279; E-mail:msthomas@wfubmc.edu. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 September 25. Published in final edited form as:Biochemistry. -I (3,6,7). In this form, the conformation of ...

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Conformational Adaptation of Apolipoprotein A-I to Discretely Sized Phospholipid Complexes

et al. 2007

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“…20,23,24 Effect of fenofibrate on the expression of genes that may affect the synthesis of HDL Current advances in HDL research indicate that the initial step in the biogenesis of HDL is the extracellular lipidation of lipid-poor ApoA-I by the action of ABCA1 lipid transporter. 45 Important steps for the maturation of HDL are the esterification of HDL of the nascent particles by Lcat, the transfer of lipids by Pltp, the cholesteryl ester transfer protein and the interaction of the HDL with the HDL receptor (SR-BI) and the ABCG1 lipid transporter. 28,35,45 The fenofibrate treatment significantly downregulated (9.75-fold) the expression of Apoa4 gene.…”

Section: Discussionmentioning

confidence: 99%

“…45 Important steps for the maturation of HDL are the esterification of HDL of the nascent particles by Lcat, the transfer of lipids by Pltp, the cholesteryl ester transfer protein and the interaction of the HDL with the HDL receptor (SR-BI) and the ABCG1 lipid transporter. 28,35,45 The fenofibrate treatment significantly downregulated (9.75-fold) the expression of Apoa4 gene. A 10-fold decrease in the Apoa4 gene expression was previously observed in the rat liver by clofibrate treatment.…”

Section: Discussionmentioning

confidence: 99%

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

et al. 2009

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We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and b-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

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“…The clinical relevance of this experiment can be further investigated by using 2DGE as a comparative tool between ''healthy'' and ''diseased'' samples. Lipoproteindeficient serum is commercially available and could be used as a model disease sample related to lipoprotein metabolism (high-density lipoprotein biosynthesis) and cardiovascular health [8]. The addition of detailed protein quantitation assays [9] and an examination of various protein staining methods could further expand the boundaries of this experiment to mirror commonly accepted practices in the proteomics research area.…”

Section: Additional Experimentsmentioning

confidence: 99%

Introducing proteomics in the undergraduate curriculum: A simple 2D gel electrophoresis exercise with serum proteins

Kim

Craig

2010

Biochem Molecular Bio Educ

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Two-dimensional gel electrophoresis (2DGE) remains an important tool in the study of biological systems by proteomics. While the use of 2DGE is commonplace in research publications, there are few instructional laboratories that address the use of 2DGE for analyzing complex protein samples. One reason for this lack is the fact that the preparation of samples for 2DGE is a complex and difficult process that can commonly yield gels of poor quality and resolution. In this experiment, we use a serum-based sample to mitigate many of the sample preparation issues that occur in cell-based sample preparations and incorporate a protein precipitation method that was developed to address the problem of high-abundance proteins and dynamic range in serum proteomics research. By focusing on 2DGE apart from many other facets of proteomic experimental design, students have the opportunity to gain fruitful experience in the use of this workhorse proteomics technique. This simplified focus also makes this exercise accessible to biochemistry instructors who are not active in proteomics; the requisite techniques may require some new equipment (i.e. an isoelectric focusing apparatus), but this exercise focuses on using familiar techniques (primarily electrophoresis) to cross the threshold of a new field, proteomics.

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Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL

Cited by 345 publications

References 217 publications

Conformational Adaptation of Apolipoprotein A-I to Discretely Sized Phospholipid Complexes

Conformational Adaptation of Apolipoprotein A-I to Discretely Sized Phospholipid Complexes

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

Introducing proteomics in the undergraduate curriculum: A simple 2D gel electrophoresis exercise with serum proteins

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