Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

Wiersma, Harmen; Gatti, Alberto; Nijstad, Niels; Elferink, Ronald P.J. Oude; Kuipers, Folkert; Tietge, Uwe J. F.

doi:10.1002/hep.23112

Cited by 79 publications

(91 citation statements)

References 39 publications

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“…SR-BI is highly-expressed in the liver and plays a fundamental role in reverse cholesterol transport mediating selective uptake of cholesteryl esters and promoting biliary cholesterol secretion [34–36]. Loss-of-function variants in human SCARB1 (SR-BI) were associated with increased in circulating HDL-C levels [37].…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

Allen

Zhao

Solano

et al. 2018

J of Extracellular Vesicle

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To comprehensively study extracellular small RNAs (sRNA) by sequencing (sRNA-seq), we developed a novel pipeline to overcome current limitations in analysis entitled, “Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER)”. To demonstrate the power of this tool, sRNA-seq was performed on mouse lipoproteins, bile, urine and livers. A key advance for the TIGER pipeline is the ability to analyse both host and non-host sRNAs at genomic, parent RNA and individual fragment levels. TIGER was able to identify approximately 60% of sRNAs on lipoproteins and >85% of sRNAs in liver, bile and urine, a significant advance compared to existing software. Moreover, TIGER facilitated the comparison of lipoprotein sRNA signatures to disparate sample types at each level using hierarchical clustering, correlations, beta-dispersions, principal coordinate analysis and permutational multivariate analysis of variance. TIGER analysis was also used to quantify distinct features of exRNAs, including 5ʹ miRNA variants, 3ʹ miRNA non-templated additions and parent RNA positional coverage. Results suggest that the majority of sRNAs on lipoproteins are non-host sRNAs derived from bacterial sources in the microbiome and environment, specifically rRNA-derived sRNAs from Proteobacteria. Collectively, TIGER facilitated novel discoveries of lipoprotein and biofluid sRNAs and has tremendous applicability for the field of extracellular RNA.

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Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

Allen

Zhao

Solano

et al. 2018

J of Extracellular Vesicle

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“…This occurred independently of SR-BI, previously reported to mediate biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. 9,10 To test the possibility that P2Y 13 is involved in RCT in vivo, [ 3 H]cholesterol-loaded peritoneal macrophages from C57BL6/J mice were injected intraperitoneally in P2Y 13 (À/À) and (þ/þ) mice. The kinetics of [ 3 H] counts in plasma were not significantly changed in P2Y 13 (À/À) mice versus (þ/þ) control mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

P2Y13 Receptor Is Critical for Reverse Cholesterol Transport

et al. 2010

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A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote ''reverse cholesterol transport'' (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y 13 (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y 13 as a target to promote RCT has not been documented. Here, we show that P2Y 13 -deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y 13 -deficient mice. Furthermore, cangrelor, a partial agonist of P2Y 13 , stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BIknockout liver ) but had no effect in P2Y 13 knockout mice, which indicate that P2Y 13 -mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake. Conclusion: These results establish P2Y 13 as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT.

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“…This expression pattern allows ABCG5/8 to promote sterol excretion in the bile and to prevent sterol uptake from the intestinal lumen. ABCG5/8 knockout mice displayed a 75% decrease in biliary cholesterol excretion, which showed a large but not exclusive role for ABCG5/8 in biliary cholesterol transport (the remaining 25% was partly transported by canalicular scavenger receptor B1) (Yu et al, 2002a;Klett et al, 2004;Wiersma et al, 2009;Dikkers et al, 2013). These mice do not display a severe cholestatic phenotype like ABCB4 knockout mice, which indicates that mixed micelle formation remains adequate in the absence of this transporter (Yu et al, 2002a;Klett et al, 2004;Wiersma et al, 2009;Dikkers et al, 2013).…”

Section: Abcg5/8mentioning

confidence: 93%

The Role of Canalicular ABC Transporters in Cholestasis

et al. 2014

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Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

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Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

Cited by 79 publications

References 39 publications

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

P2Y13 Receptor Is Critical for Reverse Cholesterol Transport

The Role of Canalicular ABC Transporters in Cholestasis

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