Oxysterols: Sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis

Brown, Andrew; Jessup, Wendy

doi:10.1016/j.mam.2009.02.005

Cited by 268 publications

(230 citation statements)

References 79 publications

(90 reference statements)

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“…Menaquinone is a known ligand for the nuclear receptor SXR (Tabb et al, 2003;Shearer and Newman, 2008;Zhou et al, 2009). SXR is known to heterodimerize with RXR and cross regulate LXR target genes that have wellestablished roles in modulation of cellular cholesterol efflux (Landes et al, 2003;Sonoda et al, 2005;Wang and Rader, 2007;Wang et al, , 2008bLim and Huang, 2008;Brown and Jessup, 2009;Zhou et al, 2009). Elevation of TERE1 would be predicted to increase cholesterol efflux and reduce cell cholesterol, consistent with our observations.…”

Section: Tere1 Modulation Of Cholesterolsupporting

confidence: 81%

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The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

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Section: Tere1 Modulation Of Cholesterolsupporting

confidence: 81%

“…Evidence links oxidative stress to the invasive phenotype in breast and pancreatic cancer (Silva et al, 2003;Brown and Jessup, 2009;Ishikawa et al, 2010). An inherent corollary to oxidative stress relates to its tolerance and the potentially heightened vulnerability of tumor cells to further increases in ROS levels (Pani et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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“…Conversely, these (apparently conflicting) results together suggest that 24SOH may play an auxiliary but not an obligatory role in affecting cholesterol metabolism and amyloid biology. Based on other evidence, Brown and Jessup (49) have independently proposed that a given oxysterol may play auxiliary but not obligatory roles in regulating cellular cholesterol homeostasis.…”

Section: Discussionmentioning

confidence: 99%

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Bryleva

Rogers

Chang

et al. 2010

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

175

193

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Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.Alzheimer disease | cholesterol esterification | lipid metabolism | oxysterols

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“…biology (37); that is, under certain conditions, the effects of 24SOH on cellular sterol homeostasis and on amyloid pathology may be replaceable by a different oxysterol, and/or by a nonoxysterol. Recently, Brown and Jessup, based on completely different experimental data, have also proposed that a given oxysterol may play auxiliary but not obligatory roles in regulating cellular cholesterol homeostasis (12).…”

Section: Roles Of Oxysterols In Vivomentioning

confidence: 99%

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

Chang

Bryleva

et al. 2010

IUBMB Life

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SummaryCholesterol has been implicated in various neurodegenerative diseases. Here we review the connection between cholesterol and Alzheimer's disease (AD), focusing on a recent study that links neuronal cholesterol esterification with biosynthesis of 24(S)-hydroxycholesterol and the fate of human amyloid precursor protein in a mouse model of AD. We also briefly evaluate the potential of ACAT1 as a drug target for AD.

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Oxysterols: Sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis

Cited by 268 publications

References 79 publications

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

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