3β,5α,6β-Cholestanetriol and 25-hydroxycholesterol accumulate in ATP-binding cassette transporter G1 (ABCG1)-deficiency

Engel, Thomas; Fobker, Manfred; Buchmann, J.; Kannenberg, Frank; Rust, Stephan; Nofer, Jerzy–Roch; Schürmann, Annette; Seedorf, Udo

doi:10.1016/j.atherosclerosis.2014.04.023

Cited by 13 publications

(8 citation statements)

References 44 publications

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“…The primary product of cholesterol autoxidation is cholesterol-5,6-epoxide (5,6-EC), which is then cleaved either enzymatically or nonenzymatically to give CT ( 15,(33)(34)(35). Moreover, a recent study suggested that CT would be a substrate for ABCG1 ( 36 ) involved in cellular export of oxysterols, sterols, phospholipids, and sphingomyelin, suggesting that ABCG1 would act as an oxysterol detoxifi cation system removing CT from cells. All these fi ndings could explain the high plasma levels of CT in these patients, which would result from intracellular 5,6-EC accumulation, their hydrolysis into CT, and their effl ux to plasma via ABCG1.…”

Section: Sensitivity and Specifi Citymentioning

confidence: 99%

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Pajares

Arias

García‐Villoria

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org Niemann-Pick type C (NPC; MIM#257220) is a progressive neurodegenerative disease caused by a disorder in the intracellular traffi cking of cholesterol that leads to a lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids in many tissues ( 1-3 ). The detection of free cholesterol accumulation by fi lipin staining in fibroblasts has been for many years the gold standard methodology for the biochemical diagnosis of the disease. This method has good sensitivity and specifi city. However, juvenile or adult onset forms sometimes present interpretation diffi culties ( 4 ). In addition, the method involves an invasive skin biopsy and the culture of fi broblasts that requires several weeks for the cellular growth, which delays the diagnosis. Some studies in cellular and animal models showed a correlation between lipid accumulation and cellular oxidative stress that produces an increase of reactive oxygen species and lipid peroxidation ( 5-8 ). In the NPC murine model, an increase of two oxysterols, cholestane-3 b ,5 a ,6 b -triol (CT) and 7-ketocholesterol (7-KC), has been observed ( 8 ). This evidence was later confi rmed in NPC patients (8)(9)(10)(11)(12)(13), showing a correlation between the oxysterol profi le and the age of onset and severity of the disease ( 8,14 ). Moreover, CT specifi cally has been found to be increased in NPC disease compared with other lysosomal and neurodegenerative diseases ( 8 ). These results Abstract Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterifi ed cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specifi city of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 pa- 26,26,26,27,27, ; AUC, area under receiver-operating characteristic curve; BHT, butylhydroxytoluene; CI, confi dence interval; CT, cholestane-3 b ,5 a ,6 b -triol; 5 a ,26,26,26,27,27, ; CTX, cerebrotendinous xanthomatosis; % CV, percentage coeffi cient of variation; LAL, lysosomal acid lipase; LOD, limit of detection; LOQ, limit of quantifi cation; LSD, lysosomal storage disease; MRM, multiple reaction monitoring; NPC, Niemann-Pick type C; ROC, receiver-operating characteristic; SLO, Smith-Lemli-Opitz.

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Section: Sensitivity and Specifi Citymentioning

confidence: 99%

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Pajares

Arias

García‐Villoria

et al. 2015

Journal of Lipid Research

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“…Also of note, ABCG1 knock-out mice showed a prominent accumulation of 24-OHC, 25-OHC and 27-OHC in the lung tissue (51). In ABCG1 overexpressing cells, these oxysterols with hydroxyl groups at the terminal end were effluxed more efficiently than oxysterols with hydroxylated C-atoms in the ring structure (62).…”

Section: Discussionmentioning

confidence: 94%

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

Yalçinkaya

Kerksiek

Gebert

et al. 2020

Journal of Lipid Research

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Loss of pancreatic β-cell mass and function as a result of sustained endoplasmic reticulum (ER) stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca 2+ -ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the hedgehog signaling receptor Smoothened (Smo) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced βcell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (24-OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and-in cells lacking ATP-binding cassette transporter ABCG1 or the 24-OHC synthesizing enzyme CYP46A1-restored the protective activity of HDL. Inhibition of Smo countered the beneficial effects of HDL but also LDL, and Smo agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the Smo-activated transcription factor gliomaassociated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation and mobilization of oxysterols for activation of the hedgehog signalling receptor Smo.

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“…Although others potential partners for ABCG1 may exist, it is very likely that ABCG1 mainly acts as a homodimer since ABCG1 and ABCG4 are generally spatially separated at the exception of the brain [ 45 ]. Human ABCG1 was identified as a lipid transporter able to promote the export of numerous lipid species including cholesterol, phospholipids (phosphatidylcholine), sphingomyelin (SM) and oxysterols (7-ketocholesterol, 7β-hydroxycholesterol and 25-hydroxycholesterol) [ 36 , 38 , 46 , 47 , 48 , 49 , 50 ]. However, it appears that ABCG1 exerts a broader array of substrates which is not restricted to lipids as ABCG1 can equally promote export of liposoluble molecules such as vitamin E (α- and γ-tocopherol) [ 51 ].…”

Section: Functions and Mechanism Of Actionmentioning

confidence: 99%

“…Importantly, lipidation of ApoA-I by ABCA1 generates nascent or preβ-HDL which may serve as a substrate for ABCG1 indicating that ABCA1 and ABCG1 act sequentially to export cellular cholesterol efflux [ 38 , 46 ]. However, even if HDL is the most efficient lipid acceptor for promoting lipid efflux through ABCG1, the latter may also occur in the presence of non-specific acceptors such as serum albumin although to a lesser degree considering the efflux of cholesterol [ 36 , 50 ].…”

Section: Functions and Mechanism Of Actionmentioning

confidence: 99%

“…By contrast, results from the genotyping of ABCG1 SNPs in CAD patients or in case-control studies for CAD support the contention that ABCG1 might exert a pro-atherogenic effect locally in the arterial wall independently of any modulation of circulating HDL-C or TG levels [ 100 ]. Such a deleterious role could result from the critical contribution of human ABCG1 in reducing macrophage apoptosis through efflux of oxysterol [ 50 , 101 ] and in promoting macrophage lipid accumulation through modulation of LPL activity in a TG-rich metabolic context [ 65 ]. In contrast to what is proposed in mice, human ABCG1 does not promote macrophage cholesterol efflux to HDL [ 52 ] and therefore is not expected to attenuate foam cell formation in early atherosclerosis lesions.…”

Section: Abcg1: Role In Atherosclerosis and Cardiovascular Diseasementioning

confidence: 99%

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Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

Hardy

Frisdal

Goff

2017

IJMS

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ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export of lipids, including cholesterol, phospholipids, sphingomyelin and oxysterols, and plays a key role in the maintenance of tissue lipid homeostasis. Although ABCG1 was initially proposed to mediate cholesterol efflux from macrophages and then to protect against atherosclerosis and cardiovascular diseases (CVD), it becomes now clear that ABCG1 exerts a larger spectrum of actions which are of major importance in cardiometabolic diseases (CMD). Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is now a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity, which are major risk factors of CVD. In order to provide the current understanding of the action of ABCG1 in CMD, we here reviewed major findings obtained from studies in mice together with data from the genetic and epigenetic analysis of ABCG1 in the context of CMD.

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3β,5α,6β-Cholestanetriol and 25-hydroxycholesterol accumulate in ATP-binding cassette transporter G1 (ABCG1)-deficiency

Cited by 13 publications

References 44 publications

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases

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