scholarly journals Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthew B. Wright ◽  
Javier Varona Santos ◽  
Christian Kemmer ◽  
Cyrille Maugeais ◽  
Jean-Philippe Carralot ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cholesterol Efflux ◽  
Cholesterol Homeostasis ◽  
Renal Diseases ◽  
Alternative Mechanism ◽  
Cellular Cholesterol ◽  
Oxysterol Binding Protein ◽  
Key Factor ◽  
Cellular Cholesterol Efflux

AbstractImpaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.

Study of ATP-binding Cassette Transporter A1 (ABCA1)-mediated Cellular Cholesterol Efflux in Diabetic Golden Hamsters

2007 ◽  
Vol 35 (4) ◽  
pp. 508-516 ◽  
Author(s):  
Y Zhu ◽  
H-J Wang ◽  
L-F Chen ◽  
Q Fang ◽  
X-W Yan
Keyword(s):  
Cholesterol Efflux ◽  
Adenosine Monophosphate ◽  
Peritoneal Macrophages ◽  
Atp Binding ◽  
Cellular Cholesterol ◽  
Golden Hamsters ◽  
Atp Binding Cassette Transporter ◽  
Cellular Cholesterol Efflux ◽  
Atp Binding Cassette

The effects of cyclic adenosine monophosphate (cAMP) and atorvastatin on macrophage adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux were investigated in a diabetic animal model. Golden hamsters were fed a high-fat diet which resulted in insulin resistance. Diabetes was induced by a single intraperitoneal injection of streptozotocin (30 mg/kg). Normal golden hamsters were used as controls. Peritoneal macrophages were incubated with apolipoprotein A-1 (apoA-1), 8-bromoadenosine-3′,5′-cyclic monophosphate (8-br-cAMP), and atorvastatin in vitro Intracellular cholesterol accumulation was greater in the diabetic animals than in the insulin-resistant animals. Expression of ABCA1 mRNA in macrophages from diabetic animals was upregulated by 8-br-cAMP and atorvastatin. ApoA-1 caused a time-dependent cellular cholesterol efflux. Both atorvastatin and 8-br-cAMP significantly facilitated ABCA1-mediated cellular cholesterol efflux, with the maximal cholesterol efflux rate observed in the macrophages from diabetic animals. Accumulation of cholesterol in the macrophages of diabetic animals can be significantly alleviated by atorvastatin or 8-br-cAMP through improving ABCA1-mediated cellular cholesterol efflux.

scholarly journals Tweaking the cholesterol efflux capacity of reconstituted HDL

2012 ◽  
Vol 90 (5) ◽  
pp. 636-645 ◽  
Author(s):  
Cheng-I J. Ma ◽  
Jennifer A. Beckstead ◽  
Airlia Thompson ◽  
Anouar Hafiane ◽  
Rui Hao Leo Wang ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Intervention Strategy ◽  
Density Lipoprotein ◽  
Cellular Cholesterol ◽  
Bhk Cells ◽  
Plasma High Density ◽  
Competing Interaction ◽  
Cellular Cholesterol Efflux

Mechanisms to increase plasma high-density lipoprotein (HDL) or to promote egress of cholesterol from cholesterol-loaded cells (e.g., foam cells from atherosclerotic lesions) remain an important target to regress heart disease. Reconstituted HDL (rHDL) serves as a valuable vehicle to promote cellular cholesterol efflux in vitro and in vivo. rHDL were prepared with wild type apolipoprotein (apo) A-I and the rare variant, apoA-I Milano (M), and each apolipoprotein was reconstituted with phosphatidylcholine (PC) or sphingomyelin (SM). The four distinct rHDL generated were incubated with CHO cells, J774 macrophages, and BHK cells in cellular cholesterol efflux assays. In each cell type, apoA-I(M) SM-rHDL promoted the greatest cholesterol efflux. In BHK cells, the cholesterol efflux capacities of all four distinct rHDL were greatly enhanced by increased expression of ABCG1. Efflux to PC-containing rHDL was stimulated by transfection of a nonfunctional ABCA1 mutant (W590S), suggesting that binding to ABCA1 represents a competing interaction. This interpretation was confirmed by binding experiments. The data show that cholesterol efflux activity is dependent upon the apoA-I protein employed, as well as the phospholipid constituent of the rHDL. Future studies designed to optimize the efflux capacity of therapeutic rHDL may improve the value of this emerging intervention strategy.

Caveolin-1 and regulation of cellular cholesterol homeostasis

2006 ◽  
Vol 291 (2) ◽  
pp. H677-H686 ◽  
Author(s):  
Philippe G. Frank ◽  
Michelle W.-C. Cheung ◽  
Stephanos Pavlides ◽  
Gemma Llaverias ◽  
David S. Park ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Free Cholesterol ◽  
Scavenger Receptor ◽  
Cholesterol Homeostasis ◽  
Type I ◽  
Wild Type ◽  
Cellular Cholesterol ◽  
Caveolin 1 ◽  
Intracellular Cholesterol ◽  
Cellular Cholesterol Efflux

Caveolae are 50- to 100-nm cell surface plasma membrane invaginations present in terminally differentiated cells. They are characterized by the presence of caveolin-1, sphingolipids, and cholesterol. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled to limit and prevent cholesterol accumulation and eventually atherosclerosis. We have recently generated caveolin-1-deficient [Cav-1(−/−)] mice in which caveolae organelles are completely eliminated from all cell types, except cardiac and skeletal muscle. In the present study, we examined the metabolism of cholesterol in wild-type (WT) and Cav-1(−/−) mouse embryonic fibroblasts (MEFs) and mouse peritoneal macrophages (MPMs). We observed that Cav-1(−/−) MEFs are enriched in esterified cholesterol but depleted of free cholesterol compared with their wild-type counterparts. Similarly, Cav-1(−/−) MPMs also contained less free cholesterol and were enriched in esterified cholesterol on cholesterol loading. In agreement with this finding, caveolin-1 deficiency was associated with reduced free cholesterol synthesis but increased acyl-CoA:cholesterol acyl-transferase (ACAT) activity. In wild-type MPMs, we observed that caveolin-1 was markedly upregulated on cholesterol loading. Despite these differences, cellular cholesterol efflux from MEFs and MPMs to HDL was not affected in the Cav-1-deficient cells. Neither ATP-binding cassette transporter G1 (ABCG1)- nor scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux was affected. Cellular cholesterol efflux to apolipoprotein A-I was not significantly reduced in Cav-1(−/−) MPMs compared with wild-type MPMs. However, ABCA1-mediated cholesterol efflux was clearly more sensitive to the inhibitory effects of glyburide in Cav-1(−/−) MPMs versus WT MPMs. Taken together, these findings suggest that caveolin-1 plays an important role in the regulation of intracellular cholesterol homeostasis and can modulate the activity of other proteins that are involved in the regulation of intracellular cholesterol homeostasis.

scholarly journals Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts

2001 ◽  
Vol 42 (2) ◽  
pp. 249-257 ◽  
Author(s):  
Bassam Haidar ◽  
Stephanie Mott ◽  
Betsie Boucher ◽  
Ching Yin Lee ◽  
Michel Marcil ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Signaling Molecules ◽  
Tangier Disease ◽  
Cellular Cholesterol ◽  
Cellular Cholesterol Efflux

Decreased cellular cholesterol efflux is a common cause of familial hypoalphalipoproteinemia: role of the ABCA1 gene mutations

2000 ◽  
Vol 152 (2) ◽  
pp. 457-468 ◽  
Author(s):  
Stephanie Mott ◽  
Lu Yu ◽  
Michel Marcil ◽  
Betsie Boucher ◽  
Colette Rondeau ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Gene Mutations ◽  
Cellular Cholesterol ◽  
Common Cause ◽  
Abca1 Gene ◽  
Cellular Cholesterol Efflux

scholarly journals Serum Amyloid A Promotes Cholesterol Efflux Mediated by Scavenger Receptor B-I

2005 ◽  
Vol 280 (43) ◽  
pp. 35890-35895 ◽  
Author(s):  
Deneys R. van der Westhuyzen ◽  
Lei Cai ◽  
Maria C. de Beer ◽  
Frederick C. de Beer
Keyword(s):  
Acute Phase ◽  
Cholesterol Efflux ◽  
Serum Amyloid A ◽  
Acute Phase Protein ◽  
Scavenger Receptor ◽  
Dependent Manner ◽  
Cellular Cholesterol ◽  
Amyloid A ◽  
Phase Protein ◽  
Cellular Cholesterol Efflux

Serum amyloid A (SAA) is an acute phase protein whose expression is markedly up-regulated during inflammation and infection. The physiological function of SAA is unclear. In this study, we reported that SAA promotes cellular cholesterol efflux mediated by scavenger receptor B-I (SR-BI). In Chinese hamster ovary cells, SAA promoted cellular cholesterol efflux in an SR-BI-dependent manner, whereas apoA-I did not. Similarly, SAA, but not apoA-I, promoted cholesterol efflux from HepG2 cells in an SR-BI-dependent manner as shown by using the SR-BI inhibitor BLT-1. When SAA was overexpressed in HepG2 cells using adenovirus-mediated gene transfer, the endogenously expressed SAA promoted SR-BI-dependent efflux. To assess the effect of SAA on SR-BI-mediated efflux to high density lipoprotein (HDL), we compared normal HDL, acute phase HDL (AP-HDL, prepared from mice injected with lipopolysaccharide), and AdSAA-HDL (HDL prepared from mice overexpressing SAA). Both AP-HDL and AdSAA-HDL promoted 2-fold greater cholesterol efflux than normal HDL. Lipid-free SAA was shown to also stimulate ABCA1-dependent cholesterol efflux in fibroblasts, in line with an earlier report (Stonik, J. A., Remaley, A. T., Demosky, S. J., Neufeld, E. B., Bocharov, A., and Brewer, H. B. (2004) Biochem. Biophys. Res. Commun. 321, 936–941). When added to cells together, SAA and HDL exerted a synergistic effect in promoting ABCA1-dependent efflux, suggesting that SAA may remodel HDL in a manner that releases apoA-I or other efficient ABCA1 ligands from HDL. SAA also facilitated efflux by a process that was independent of SR-BI and ABCA1. We conclude that the acute phase protein SAA plays an important role in HDL cholesterol metabolism by promoting cellular cholesterol efflux through a number of different efflux pathways.

scholarly journals Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

2008 ◽  
Vol 158 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Robin P F Dullaart ◽  
Albert K Groen ◽  
Geesje M Dallinga-Thie ◽  
Rindert de Vries ◽  
Wim J Sluiter ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Cholesterol Esterification ◽  
Cellular Cholesterol ◽  
Apo E ◽  
Pltp Activity ◽  
Cellular Cholesterol Efflux

ObjectiveWe tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol.DesignIn 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor.ResultsApo E, PLTP activity, EST, and CET were higher (P=0.04 to <0.001), whereas adiponectin was lower in MetS subjects (P<0.01). Pre-β-HDL and pre-β-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8±1.0 vs 8.5±0.9%,P=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (P<0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status.ConclusionsThe ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.

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