Cell cholesterol efflux: integration of old and new observations provides new insights

Rothblat, George H.; Llera-Moya, Margarita de la; Atger, V.; Kellner-Weibel, Ginny; Williams, David L.; Phillips, Michael C.

doi:10.1016/s0022-2275(20)32113-1

Cited by 443 publications

(88 citation statements)

References 92 publications

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“…In the light of these results it seems possible that downregulation of ACAT activity would represent a more direct effect of ORP2 overexpression, which would lead to increased availability of free [ 14 C]cholesterol for efflux. Consistent with our results, this should lead to an increase in both apolipoprotein-mediated and diffusion-based removal of cellular cholesterol (27)(28)(29). The mechanisms by which an excess of ORP2 affects the esterification and efflux of cellular cholesterol are at present unknown.…”

Section: Discussionsupporting

confidence: 89%

“…Mock-transfected and ORP2/CHO cells were labeled with [ 14 C]cholesterol for 36 h in culture medium containing 10% FBS, and efflux of radioactive cholesterol to human serum (20%), apoA-I (20 g/ml), or to small unilamellar PC vesicles (0.3 mg PC/ml) was measured. In the experiments measuring apoA-I mediated efflux (27)(28)(29), BSA was used as a non-specific acceptor. During the 2 h efflux period of the [ 14 C]cholesterol to human serum, a significantly higher amount of the labeled cholesterol was transferred to the acceptor from the ORP2/CHO as compared with mock-transfected cells, the relative increment being approximately 40% (Fig.…”

Section: Resultsmentioning

confidence: 99%

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ORP2, a homolog of oxysterol binding protein, regulates cellular cholesterol metabolism

Laitinen

Lehto

Lehtonen

et al. 2002

Journal of Lipid Research

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Oxysterol binding protein (OSBP) related proteins (ORPs) constitute a family that has at least 12 members in humans. In the present study we characterize one of the novel OSBP homologs, ORP2, which we show to be expressed ubiquitously in mammalian tissues. The ORP2 cDNA encodes a deduced 55 kDa protein that lacks a pleckstrin homology (PH) domain, a feature found in the other family members. Sucrose gradient centrifugation analysis of Chinese hamster ovary (CHO) cell post-nuclear supernatant demonstrated that ORP2 is distributed in soluble and membrane-bound fractions. Immunofluorescence microscopy of the endogenous and overexpressed ORP2 in CHO cells suggested that the membrane-bound fraction of the protein localizes to the Golgi apparatus. Stably transfected CHO cells that overexpress ORP2 showed an increase in [ 14 C]cholesterol efflux to serum, apolipoprotein A-I (apoA-I), and phosphatidyl choline vesicles. The proportion of cellular [ 14 C]cholesterol that is esterified and the ACAT activity measured as [ 14 C]oleyl-CoA conversion into cholesteryl [ 14 C]oleate by the cellular membranes, were markedly decreased in the ORP2 expressing cells. Transient high level overexpression of ORP2 interfered with the clearance of a secretory pathway protein marker from the Golgi complex. The results implicate ORP2 as a novel regulator of cellular sterol homeostasis and intracellular membrane trafficking.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

ORP2, a homolog of oxysterol binding protein, regulates cellular cholesterol metabolism

Laitinen

Lehto

Lehtonen

et al. 2002

Journal of Lipid Research

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“…Role in cholesterol efflux. HDL apolipoproteins located in the extracellular space are potentially important players in cholesterol efflux from peripheral cells, which is the first step of reverse cholesterol transport (48). Cholesterol efflux can occur either by a passive slow diffusion-type mechanism or by a fast specific energy-dependent mechanism that results in the transfer of cholesterol to lipid-poor apolipoproteins (49).…”

Section: Roles In Hdl Structure-function and Metabolismmentioning

confidence: 99%

“…To date, the main HDL receptor known to be related to cholesterol efflux is ATP-binding cassette transporter 1 or cholesterol efflux regulatory protein (ABC-1/CERP), whereas scavenger receptor class B type I or CD36 and LIMPII analogous 1 (SR-BI/CLA-1) may also be of importance in this process (48). Apolipoprotein acceptor specificity for lipid efflux induced by ABC-1 has been examined in stably transfected HeLa cells expressing human ABC-1 product (56).…”

Section: Roles In Hdl Structure-function and Metabolismmentioning

confidence: 99%

Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein

Blanco‐Vaca

Escolà‐Gil

Martín‐Campos

et al. 2001

Journal of Lipid Research

123

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Our understanding of apolipoprotein A-II (apoA-II) physiology is much more limited than that of apoA-I. However, important and rather surprising advances have been produced, mainly through analysis of genetically modified mice. These results reveal a positive association of apoA-II with FFA and VLDL triglyceride plasma concentrations; however, whether this is due to increased VLDL synthesis or to decreased VLDL catabolism remains a matter of controversy. As apoA-II-deficient mice present a phenotype of insulin hypersensitivity, a function of apoA-II in regulating FFA metabolism seems likely. Studies of human beings have shown the apoA-II locus to be a determinant of FFA plasma levels, and several genome-wide searches of different populations with type 2 diabetes have found linkage to an apoA-II intragenic marker, making apoA-II an attractive candidate gene for this disease. The increased concentration of apoBcontaining lipoproteins present in apoA-II transgenic mice explains, in part, why these animals present increased atherosclerosis susceptibility. In addition, apoA-II transgenic mice also present impairment of two major HDL antiatherogenic functions: reverse cholesterol transport and protection of LDL oxidative modification. The apoA-II locus has also been suggested as an important genetic determinant of HDL cholesterol concentration, even though there is a major species-specific difference between the effects of mouse and human apoA-II. As antagonizing apoA-I antiatherogenic actions can hardly be considered the apoA-II function in HDL, this remains a topic for future investigations. We suggest that the existence of apoA-II or apoA-I in HDL could be an important signal for specific interaction with HDL receptors such as cubilin or heat shock protein 60. -Blanco-Vaca, F., J. C. Escolà-Gil, J. M. Martín-Campos, and J. Julve. Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. J.

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“…Furthermore, the inhibition of ABCA1 activity in mouse spermatozoa has shown to significantly reduce the capacity for fertilization [ 38 ], thus highlighting its functional importance. On the other hand, cholesterol transport from SR-BI to HDLs is predominantly a passive process and can be bidirectional in somatic cells [ 33 , 39 ]. SR-BI has been localized in mouse and human spermatids [ 40 , 41 ], as well as mature human spermatozoa [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility

Bernecic

Graaf

Leahy

et al. 2021

Biology of Reproduction

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Reverse Cholesterol Transport or cholesterol efflux is part of an extensive plasma membrane remodelling process in spermatozoa that is imperative for fertilisation. For ram spermatozoa, sheep serum is well known to support in vitro fertilisation (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20–40% (as measured by the BODIPY-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8–15)%. Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilisation. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilisation in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF.

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Cell cholesterol efflux: integration of old and new observations provides new insights

Cited by 443 publications

References 92 publications

ORP2, a homolog of oxysterol binding protein, regulates cellular cholesterol metabolism

ORP2, a homolog of oxysterol binding protein, regulates cellular cholesterol metabolism

Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein

HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility

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