ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels

Trigueros-Motos, Laia; Capelleveen, Julian C. van; Torta, Federico; Castaño, David; Zhang, Linhua; Chai, Ee Chu; Kang, Martin H.; Dimova, Lidiya G.; Schimmel, Alinda W.M.; Tietjen, Ian; Radomski, Chris; Tan, Liang Juin; Thiam, Chung Hwee; Narayanaswamy, Pradeep; Wu, Daniel Heqing; Dorninger, Fabian; Yakala, Gopala K.; Barhdadi, Amina; Angeli, Véronique; Dubé, Marie‐Pierre; Berger, Johannes; Dallinga‐Thie, Geesje M.; Tietge, Uwe J. F.; Wenk, Markus R.; Hayden, Michael R.; Hovingh, G. Kees; Singaraja, Roshni R.

doi:10.1161/atvbaha.117.309574

Cited by 58 publications

(53 citation statements)

References 38 publications

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“…In contrast, as an example of HSAGs, ATP Binding Cassette Subfamily A Member 8 ( ABCA8 ) showed strong upregulation with age (FDR = 8.15 × 10 −3 ) in the “healthy” cohort (Figure e and Figure d), while no association was observed in the “unhealthy” cohort (FDR = 0.23). HDLc levels were found decreased by 29% ( p = .01) in ABCA8 deficiency mice on a high‐cholesterol diet compared with wild‐type mice (Trigueros‐Motos et al, ). ABC transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes (Tang et al, ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

et al. 2020

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A key goal of aging research was to understand mechanisms underlying healthy aging and develop methods to promote the human healthspan. One approach is to identify gene regulations unique to healthy aging compared with aging in the general population (i.e., “common” aging). Here, we leveraged Genotype‐Tissue Expression (GTEx) project data to investigate “healthy” and “common” aging gene expression regulations at a tissue level in humans and their interconnection with diseases. Using GTEx donors' disease annotations, we defined a “healthy” aging cohort for each tissue. We then compared the age‐associated genes derived from this cohort with age‐associated genes from the “common” aging cohort which included all GTEx donors; we also compared the “healthy” and “common” aging gene expressions with various disease‐associated gene expressions to elucidate the relationships among “healthy,” “common” aging and disease. Our analyses showed that 1. GTEx “healthy” and “common” aging shared a large number of gene regulations; 2. Despite the substantial commonality, “healthy” and “common” aging genes also showed distinct function enrichment, and “common” aging genes had a higher enrichment for disease genes; 3. Disease‐associated gene regulations were overall different from aging gene regulations. However, for genes regulated by both, their regulation directions were largely consistent, implying some aging processes could increase the susceptibility to disease development; and 4. Possible protective mechanisms were associated with some “healthy” aging gene regulations. In summary, our work highlights several unique features of GTEx “healthy” aging program. This new knowledge could potentially be used to develop interventions to promote the human healthspan.

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Section: Resultsmentioning

confidence: 99%

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

et al. 2020

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“…After data filtering, a novel nonsense mutation (NM_007168: c.3460C>T; p.R1154X) of ABCA8 was identified and validated by Sanger sequencing in the proband (Figure 1E). Previous studies have revealed that deleterious heterozygous ABCA8 mutations may disrupt cholesterol efflux and reduce HDL-c levels in humans and mice (Trigueros-Motos et al, 2017;Sasaki et al, 2018). No other meaningful mutations related to lipid metabolism has been identified.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

“…However, the underlying cause of reduced HDL-c values was still not clear. Several genes including ATP binding cassette subfamily A member 1 (ABCA1) and ATP binding cassette subfamily A member 8 (ABCA8) have been identified in patients with reduced HDL-c (Trigueros-Motos et al, 2017;Maranghi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A Novel Nonsense Mutation of ABCA8 in a Han-Chinese Family With ASCVD Leads to the Reduction of HDL-c Levels

et al. 2020

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Arteriosclerotic cardiovascular disease (ASCVD) is one of the major causes of death worldwide and most commonly develops as a result of atherosclerosis (AS). As we all know, dyslipidemia is a leading pathogenic risk factor for ASCVD, which leads to cardiac ischemic injury and myocardial infarction. Dyslipidemias include hypercholesterolemia, hypertriglyceridemia, increased low-density lipoprotein cholesterol (LDL-c) and decreased high density lipoproteins cholesterol (HDL-c). Mutations of dyslipidemia related genes have been proved to be the crucial contributor to the development of AS and ASCVD. In this study, a Han-Chinese family with ASCVD was enrolled and the lipid testing discovered an obvious reduced levels of HDL-c in the affected members. We then performed whole exome sequencing to detect the candidate genes of the family. After data filtering, a novel heterozygous nonsense mutation (NM_007168: c.3460C>T; p.R1154X) of ABCA8 was detected and validated to be co-separated in the family members by Sanger sequencing. Previous studies have proved that deleterious heterozygous ABCA8 variants may disrupt cholesterol efflux and reduce HDL-c levels in humans and mice. This study may be the second report related to ABCA8 mutations in patients with reduced levels of HDL-c. Our study not only contributed to the genetic counseling and prenatal genetic diagnosis of patients with ASCVD caused by reduced HDL-c levels, but also provided a new sight among ABCA8, cholesterol efflux and HDL-c levels.

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“…Additional ABCA family proteins are involved in cholesterol efflux. ABCA8 facilitates cholesterol efflux to apoA-I and modulates HDL-cholesterol levels ( 192 ). In humans, mutations in this gene are associated with low HDL-cholesterol levels ( 192 ).…”

Section: Sterol Export To Extracellular Milieumentioning

confidence: 99%

“…ABCA8 facilitates cholesterol efflux to apoA-I and modulates HDL-cholesterol levels ( 192 ). In humans, mutations in this gene are associated with low HDL-cholesterol levels ( 192 ). In addition, ABCA12 also regulates cholesterol efflux ( 193 ).…”

Section: Sterol Export To Extracellular Milieumentioning

confidence: 99%

Sterol Metabolism and Transport in Atherosclerosis and Cancer

Yamauchi

Rogers

2018

Front. Endocrinol.

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Cholesterol is a vital lipid molecule for mammalian cells, regulating fluidity of biological membranes, and serving as an essential constituent of lipid rafts. Mammalian cells acquire cholesterol from extracellular lipoproteins and from de novo synthesis. Cholesterol biosynthesis generates various precursor sterols. Cholesterol undergoes metabolic conversion into oxygenated sterols (oxysterols), bile acids, and steroid hormones. Cholesterol intermediates and metabolites have diverse and important cellular functions. A network of molecular machineries including transcription factors, protein modifiers, sterol transporters/carriers, and sterol sensors regulate sterol homeostasis in mammalian cells and tissues. Dysfunction in metabolism and transport of cholesterol, sterol intermediates, and oxysterols occurs in various pathophysiological settings such as atherosclerosis, cancers, and neurodegenerative diseases. Here we review the cholesterol, intermediate sterol, and oxysterol regulatory mechanisms and intracellular transport machineries, and discuss the roles of sterols and sterol metabolism in human diseases.

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ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels

Abstract: ABCA8 facilitates cholesterol efflux and modulates HDLc levels in humans and mice.

Cited by 58 publications

References 38 publications

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

A Novel Nonsense Mutation of ABCA8 in a Han-Chinese Family With ASCVD Leads to the Reduction of HDL-c Levels

Sterol Metabolism and Transport in Atherosclerosis and Cancer

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