The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism

Davis, Warren

doi:10.1016/j.bbalip.2013.10.019

Cited by 24 publications

(17 citation statements)

References 43 publications

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“…Present studies suggest that disorders of cholesterol metabolism are associated with A␤ production and AD onset [2][3][4]. Raised cholesterol levels stimulate ␤-and ␥-secretases, which catalyze amyloid precursor protein (APP) cleavage, generating many pathological A␤ segments, of which, the A␤ oligomer has the greatest impact.…”

Section: Discussionmentioning

confidence: 99%

SORL1 gene polymorphism association with late-onset Alzheimer’s disease

Feng

Hou

Deng

et al. 2015

Neuroscience Letters

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Section: Discussionmentioning

confidence: 99%

SORL1 gene polymorphism association with late-onset Alzheimer’s disease

Feng

Hou

Deng

et al. 2015

Neuroscience Letters

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“…Cells were grown in DMEM/Ham’s F12 (50:50) supplemented with 5% fetal bovine serum (FBS) 2 mM glutamine and 1% Penstrep at 37° C and 5% CO 2 . N2a cell lines stably expressing a 7.4-kilobase human ABCA2 cDNA in the pcDNA5/FRT/TO vector (Invitrogen) have been previously described [18, 19, 23]. …”

Section: Methodsmentioning

confidence: 99%

“…The ABCA2 expression level in neural cells was associated with changes in the mass of many ceramide species as well as ceramide metabolites [23]. …”

Section: Introductionmentioning

confidence: 99%

The ATP-Binding Cassette Transporter-2 (ABCA2) Overexpression Modulates Sphingosine Levels and Transcription of the Amyloid Precursor Protein (APP) Gene

Davis

2015

CAR

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The ATP-binding cassette transporter-2 (ABCA2) is a member of a family of multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. ABCA2 has also been genetically linked with Alzheimer’s disease but the molecular mechanisms are unknown. In this report, we hypothesized that ABCA2 modulation of sphingolipid metabolism activates a signaling pathway that regulates amyloid precursor protein transcription. We found that ABCA2 overexpression in N2a cells was associated with increased mass of the sphingolipid sphingosine, derived from the catabolism of ceramide. ABCA2 overexpression increased in vitro alkaline and acid ceramidase activity. Sphingosine is a physiological inhibitor of protein kinase C (PKC) activity. Pharmacological inhibition of ceramidase activity or activation PKC activity with 12-myristate 13-acetate (PMA) or diacylglycerol (DAG) decreased endogenous APP mRNA levels in ABCA2 overexpressing cells. Treatment with PMA also decreased the expression of a transfected human APP promoter reporter construct, while treatment with a general PKC inhibitor, GF109203x, increased APP promoter activity. In N2a cells, chromatin immunoprecipitation experiments revealed that a repressive complex forms at the AP-1 site in the human APP promoter, consisting of c-jun, c-jun dimerization protein 2 (JDP2) and HDAC3 and this complex was reduced in ABCA2 overexpressing cells. Activation of the human APP promoter in A2 cells was directed by the upstream stimulatory factors USF-1 and USF-2 that bound to an E-box element in vivo. These findings indicate that ABCA2 overexpression modulates sphingosine levels and regulates transcription of the endogenous APP gene.

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“…Sphingolipids have many biological functions, including cell membrane formation, signal transduction, and lipid metabolism [17] . There is evidence that sphingolipids serves bioactive lipid mediators that regulate ABC transporters [18,19] . Ceramide, the hydrolytic product of sphingomyelin, also was reported as a second messenger for cellular functions ranging from proliferation to apoptosis [6] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ceramide Decreased the Expression of ATP-Binding Cassette Transporter G5/8 mRNA in an Animal Model of Cholesterol Gallstone

Kim

et al. 2017

Dig Dis

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Background: The increased risk of gallstone has been reported in patients with ATP-binding cassette (ABC) transporter polymorphism. The half-transporters ABCG5 and ABCG8 mediate the efflux of cholesterol in hepatocytes and the intestine. We investigated whether ceramide plays a role in cholesterol efflux through the ABC transporters. Methods: Six-week-old C57BL/6J mice were assigned to 3 groups. The normal group (n = 5) was fed a normal chow diet, the cholesterol group (n = 10) was fed a lithogenic diet, and the myriocin group (n = 15) was fed the lithogenic diet and myriocin, a specific inhibitor of serine-palmitoyl transferase. After 6 weeks, the ABCG5 and ABCG8 transporters were analyzed. Results: The rate of cholesterol gallstone formation in cholesterol group was also higher than that in normal and myriocin groups (0, 70, and 40%, respectively). ABCG5 and ABCG8 mRNA levels were significantly increased in cholesterol group and less increased in myriocin group, relative to that in normal group (p < 0.05). Conclusions: The inhibition of ceramide biosynthesis by myriocin suppressed gallstone formation and ABCG5/8 mRNA expression. We expect that ceramide's role as a regulator of the ABCG5/8 transporter might be linked to cholesterol gallstone formation.

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The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism

Cited by 24 publications

References 43 publications

SORL1 gene polymorphism association with late-onset Alzheimer’s disease

SORL1 gene polymorphism association with late-onset Alzheimer’s disease

The ATP-Binding Cassette Transporter-2 (ABCA2) Overexpression Modulates Sphingosine Levels and Transcription of the Amyloid Precursor Protein (APP) Gene

Inhibition of Ceramide Decreased the Expression of ATP-Binding Cassette Transporter G5/8 mRNA in an Animal Model of Cholesterol Gallstone

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