Lack of Abcg1 results in decreased plasma HDL cholesterol levels and increased biliary cholesterol secretion in mice fed a high cholesterol diet

Wiersma, Harmen; Nijstad, Niels; Boer, Jan Freark de; Out, Ruud; Hogewerf, Wytse; Berkel, Theo J van; Kuipers, Folkert; Tietge, Uwe J. F.

doi:10.1016/j.atherosclerosis.2009.02.022

Cited by 34 publications

(66 citation statements)

References 27 publications

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“…To investigate the role of P2Y 13 in cholesterol metabolism in vivo, we generated P2Y 13 -null mice (À/À) by a gene-targeting strategy (Fig. 1) and their wildtype littermates (þ/þ) were used as controls.…”

Section: Resultsmentioning

confidence: 99%

“…To examine HDL uptake mediated by P2Y 13 , we allowed endocytosis of fluorescent DyLight 549 -HDL in primary hepatocytes isolated from P2Y 13 (À/À) and (þ/þ) mice. After 30 minutes of endocytosis, fluorescent DyLight 549 -HDL showed a punctate endosomal pattern in hepatocytes from (þ/þ) mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This is a process in which excess cholesterol from peripheral tissue and macrophages/foam cells is taken up and processed in HDL particles and later delivered to the liver, before being excreted in the bile as free cholesterol or after transformation into bile acids. 1 This process, the principal way by which the body eliminates cholesterol, relies on specific interactions between HDL particles and peripheral cells (cholesterol efflux) on the one hand and hepatocytes (HDL cholesterol uptake) on the other Abbreviations: abca1, ATP-binding cassette, subfamily A, member 1; abcb4, ATP-binding cassette b4; abcb11/bsep, ATP-binding cassette b11/bile salt export pump; abcg1, ATP-binding cassette g1; abcg5/abcg8, ATP-binding cassette g5/g8; apoA-I, apolipoprotein A-I; ATP, adenosine triphosphate; HDL, high-density lipoprotein; hmgcr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; mRNA, messenger RNA; ntcp, Na þ -taurocholate cotransporting polypeptide; oatp, organic anion transport polypeptide; P2Y 13 , purinergic receptor P2Y, G-protein-coupled 13; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B, type I.…”

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confidence: 99%

“…2,3 A likely candidate mechanism mediating HDL holoparticle uptake in the absence of SR-BI is the cell-surface complex related to mitochondrial F 1 -adenosine triphosphatase (ATPase), namely ecto-F 1 -ATPase. 4 When HDL binds to apolipoprotein A-I (apoA-I), this enzyme generates extracellular adenosine diphosphate (ADP) which then specifically activates the P2Y 13 receptor which is a Gprotein-coupled receptor. This results in HDL holoparticle endocytosis mediated by as-yet unidentified low-affinity binding sites.…”

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confidence: 99%

“…This results in HDL holoparticle endocytosis mediated by as-yet unidentified low-affinity binding sites. In addition, cangrelor, which acts as a partial agonist of the P2Y 13 receptor, stimulates HDL endocytosis by human hepatocytes and perfused mouse liver. 5 In this study, we generated P2Y 13 -null mice (À/À) in order to investigate the potential contribution of P2Y 13 to RCT.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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P2Y13 receptor is critical for reverse cholesterol transport

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Metabolism

2011

High‐Density Lipoproteins

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Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

Rayego‐Mateos

Morgado‐Pascual

García‐Caballero

et al. 2023

The Journal of Pathology

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Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme‐mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD‐promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Lack of Abcg1 results in decreased plasma HDL cholesterol levels and increased biliary cholesterol secretion in mice fed a high cholesterol diet

Cited by 34 publications

References 27 publications

P2Y13 receptor is critical for reverse cholesterol transport

P2Y13 receptor is critical for reverse cholesterol transport

Metabolism

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

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