Apolipoprotein Specificity for Lipid Efflux by the Human ABCAI Transporter

Aims/hypothesis AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile. Materials and methods The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied. Results The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGEmodification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes. Conclusions/interpretation AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.

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“…HeLa cells do not express ABC transporters [28] and cholesterol efflux to lipid-free apoA-I in mock-transfected cells was minimal (Fig. 4a).…”

Section: Resultsmentioning

confidence: 99%

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

et al. 2007

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“…It is well known that many of the exchangeable helical apolipoproteins can stimulate cellular cholesterol efflux (42)(43)(44). Although speculative, the structure created by the 1/9 and 9/10 helical combinations may constitute a motif in the exchangeable apolipoproteins that facilitates the necessary interactions with the ABCA1 transporter to mediate cellular cholesterol efflux.…”

Section: Discussionmentioning

confidence: 99%

Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

Natarajan

Forte

Chu

et al. 2004

Journal of Biological Chemistry

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Synthetic peptides were used in this study to identify a structural element of apolipoprotein (apo) A-I that stimulates cellular cholesterol efflux and stabilizes the ATP binding cassette transporter A1 (ABCA1). Peptides (22-mers) based on helices 1 (amino acids 44 -65) and 10 (amino acids 220 -241) of apoA-I had high lipid binding affinity but failed to mediate ABCA1-dependent cholesterol efflux, and they lacked the ability to stabilize ABCA1. The addition of helix 9 (amino acids 209 -219) to either helix 1 (creates a 1/9 chimera) or 10 (9/10 peptide) endowed cholesterol efflux capability and ABCA1 stabilization activity similar to full-length apoA-I. Adding helix 9 to helix 1 or 10 had only a small effect on lipid binding affinity compared with the 22-mer peptides, indicating that helix length and/or determinants on the polar surface of the amphipathic ␣-helices is important for cholesterol efflux. Cholesterol efflux was specific for the structure created by the 1/9 and 9/10 helical combinations, as 33-mers composed of helices 1 and 3 (1/3), 2/9, and 4/9 failed to mediate cholesterol efflux in an ABCA1-dependent manner. Transposing helices 9 and 10 (10/9 peptide) did not change the class Y structure, hydrophobicity, or amphiphilicity of the helical combination, but the topography of negatively charged amino acids on the polar surface was altered, and the 10/9 peptide neither mediated ABCA1-dependent cholesterol efflux nor stabilized ABCA1 protein. These results suggest that a specific structural element possessing a linear array of acidic residues spanning two apoA-I amphipathic ␣-helices is required to mediate cholesterol efflux and stabilize ABCA1.

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“…ATP-binding cassette transporter A1 (ABCA1) is a key transporter of cholesterol to lipidpoor apolipoprotein A-I (apoA-I) and nascent HDL (35). Using real-time PCR, we found that ABCA1 mRNA (2.3-fold, P < 0.0001) (Fig.…”

Section: Significancementioning

confidence: 98%

MicroRNA-223 coordinates cholesterol homeostasis

Vickers

Landstreet

Levin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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228

212

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Significance Results from this study represent a breakthrough in our understanding of posttranscriptional control of cholesterol metabolism and how microRNAs (miRNAs) are at the heart of cholesterol regulatory circuitry and homeostasis. Although cells are adept at maintaining proper cholesterol levels, it was unknown how cells posttranscriptionally coordinate cholesterol uptake, efflux, and synthesis. MicroRNA-223 (miR-223) transcription and expression are maintained by cholesterol, and, as a feedback network, miR-223 inhibits cholesterol biosynthesis and uptake and increases cholesterol efflux. This study clearly demonstrates the extensive role that miRNAs play in coordinating metabolic adaptation to disease and general homeostasis. This work highlights a unique regulatory control point for cholesterol homeostasis and illustrates how important the study of miRNAs is to the greater understanding of dyslipidemia and cardiovascular disease.

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Apolipoprotein Specificity for Lipid Efflux by the Human ABCAI Transporter

Cited by 307 publications

References 28 publications

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

Identification of an Apolipoprotein A-I Structural Element That Mediates Cellular Cholesterol Efflux and Stabilizes ATP Binding Cassette Transporter A1

MicroRNA-223 coordinates cholesterol homeostasis

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