Altered lipoprotein metabolism in P2Y13 knockout mice

Blom, Daniël; Yamin, Ting-Ting; Champy, Marie‐France; Selloum, Mohammed; Bedu, Elodie; Carballo-Jane, Ester; Gerckens, Lynn S.; Luell, Silvi; Meurer, Roger; Chin, Jayne; Mudgett, John S.; Puig, Óscar

doi:10.1016/j.bbalip.2010.08.013

Cited by 33 publications

(24 citation statements)

References 30 publications

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“…The in vivo data have to be placed in light of a non-tissue-specific removal of the receptor, and the observed neuroprotection may be due to changes in lipid metabolism, altered insulin and glucose levels affecting whole body metabolism, or embryonic changes altering the prerequisites for PA-mediated neuronal loss. This is illustrated by the finding that though phenotypic analysis of P2Y 13 −/− mice did not show changed insulin sensitivity or glucose tolerance, inhibition of P2Y 13 receptor activity in mice using MRS2211 leads to increased insulin secretion and reduced plasma glucose [15,20]. However, the here presented in vitro findings excitingly Activation of the P2Y 13 receptor in mice leads to an augmented hepatic HDL uptake and bile acid secretion [21].…”

Section: Lipid-induced Neuronal Losscontrasting

confidence: 44%

“…Silencing the P2Y 13 receptor results in reduced TG-HDL endocytosis and internalization [13]. Gene profiling and phenotypic analysis of P2Y 13 −/− mice confirm that they hold altered lipoprotein, cholesterol and HDL metabolism [20]. HFD has previously been shown to increase lipid droplet accumulation in intestinal muscularis propria in C57BL/6 mice [22].…”

Section: Lipid-induced Neuronal Lossmentioning

confidence: 88%

“…Peripherally, the receptor plays key roles in lipoprotein metabolism and reverse cholesterol transport [19]. Activation of the P2Y 13 receptor reduces high-density lipoprotein (HDL) levels and increases hepatic HDL uptake in mice [13,[19][20][21]. Research obtained, either by silencing the P2Y 13 receptors through targeted gene deletion or small interfering RNA, suggests a pro-apoptotic role of P2Y 13 receptor activation.…”

Section: Introductionmentioning

confidence: 99%

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The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss

Voss

Turesson

Robaye

et al. 2014

Purinergic Signalling

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Gastrointestinal symptoms have a major impact on the quality of life and are becoming more prevalent in the western population. The enteric nervous system (ENS) is pivotal in regulating gastrointestinal functions. Purinergic neurotransmission conveys a range of short and long-term cellular effects. This study investigated the role of the ADPsensitive P2Y 13 receptor in lipid-induced enteric neuropathy. Littermate P2Y 13 +/+ and P2Y 13 −/− mice were fed with either a normal diet (ND) or high-fat diet (HFD) for 6 months. The intestines were analysed for morphological changes as well as neuronal numbers and relative numbers of vasoactive intestinal peptide (VIP)-and neuronal nitric oxide synthase (nNOS)-containing neurons. Primary cultures of myenteric neurons from the small intestine of P2Y 13 +/+ or P2Y 13 −/− mice were exposed to palmitic acid (PA), the P2Y 13 receptor agonist 2meSADP and the antagonist MRS2211. Neuronal survival and relative number of VIP-containing neurons were analysed. In P2Y 13 +/+ , but not in P2Y 13 −/− mice, HFD caused a significant loss of myenteric neurons in both ileum and colon. In colon, the relative numbers of VIP-containing submucous neurons were significantly lower in the P2Y 13 −/− mice compared with P2Y 13 +/+ mice. The relative numbers of nNOS-containing submucous colonic neurons increased in P2Y 13 +/+ HFD mice. HFD also caused ileal mucosal thinning in P2Y 13 +/+ and P2Y 13 −/− mice, compared to ND fed mice. In vitro PA exposure caused loss of myenteric neurons from P2Y 13 +/+ mice while neurons from P2Y 13 −/− mice were unaffected. Presence of MRS2211 prevented PA-induced neuronal loss in cultures from P2Y 13 +/+ mice. 2meSADP caused no change in survival of cultured neurons. P2Y 13 receptor activation is of crucial importance in mediating the HFD-and PAinduced myenteric neuronal loss in mice. In addition, the results indicate a constitutive activation of enteric neuronal apoptosis by way of P2Y 13 receptor stimulation.

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Section: Lipid-induced Neuronal Losscontrasting

confidence: 44%

Section: Lipid-induced Neuronal Lossmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss

Voss

Turesson

Robaye

et al. 2014

Purinergic Signalling

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“…All of the three P2Y receptors that are preferentially activated by ADP (P2Y 1 , P2Y 12 and P2Y 13 ) have been found to be coupled to ecto-F 1 -ATPase activity and display different functions depending on the cell type [32]. For instance, in hepatocytes the apoA-I/ecto-F 1 -ATPase/P2Y 13 axis activates an intracellular RhoA/ROCKI signaling pathway that stimulates HDL uptake and appears to have atheroprotective properties by promoting reverse cholesterol transport [21-24, 30, 44, 45], and in adipocytes HDL-apoA-I, ecto-F 1 -ATPase and P2Y signaling are all involved in lipid metabolism [46-50]. In endothelial cells, apoA-I/ecto-F 1 -ATPase has been previously shown to stimulate HDL transcytosis via activation of P2Y 12 ADP receptors [20].…”

Section: Discussionmentioning

confidence: 99%

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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Background/Aims: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F₁-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F₁-ATPase activation. Methods: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F₁-ATPase activation by apoA-I. Results: ApoA-I and HDL both induced Akt phosphorylation. F₁-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F₁-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y₁-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. Conclusion: Altogether, these data highlight a key role of the P2Y₁/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F₁-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.

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“…The extracellular ADP generated then selectively activates the P2Y13 purinergic receptor, resulting in cytoskeleton reorganization and subsequent clathrin-dependent endocytosis of whole HDL particles. P2Y13 -knockout mice displayed impaired biliary cholesterol secretions [ 64, 67- 68 ] and were prone to atherosclerosis on apoE-KO background [ 65 ] , consistent with the role of P2Y13 in HDL endocytosis by hepatocytes. Conversely, overexpression of P2Y13 in mice is atheroprotective [ 66 ] .…”

Section: Hdl-bile Acid Channelmentioning

confidence: 67%

Shunts, channels and lipoprotein endosomal traffic: a new model of cholesterol homeostasis in the hepatocyte

Kiss

Sniderman

2017

J Biomed Res

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The liver directs cholesterol metabolism in the organism. All the major fluxes of cholesterol within the body involve the liver: dietary cholesterol is directed to the liver; cholesterol from peripheral cells goes to the liver; the liver is a major site of cholesterol synthesis for the organism; cholesterol is secreted from the liver within the bile, within apoB lipoproteins and translocated to nascent HDL. The conventional model of cholesterol homeostasis posits that cholesterol from any source enters a common, rapidly exchangeable pool within the cell, which is in equilibrium with a regulatory pool. Increased influx of cholesterol leads rapidly to decreased synthesis of cholesterol. This model was developed based on in vitro studies in the fibroblast and validated only for LDL particles. The challenges the liver must meet in vivo to achieve cholesterol homeostasis are far more complex. Our model posits that the cholesterol derived from three different lipoproteins endosomes has three different fates: LDL-derived cholesterol is largely recycled within VLDL with most of the cholesterol shunted through the hepatocyte without entering the exchangeable pool of cholesterol; high density lipoprotein-derived CE is transcytosed into bile; and chylomicron remnant-derived cholesterol primarily enters the regulatory pool within the hepatocyte. These endosomal channels represent distinct physiological pathways and hepatic homeostasis represents the net result of the outcomes of these distinct channels. Our model takes into account the distinct physiological challenges the hepatocyte must meet, underlie the pathophysiology of many of the apoB dyslipoproteinemias and account for the sustained effectiveness of therapeutic agents such as statins.

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Altered lipoprotein metabolism in P2Y13 knockout mice

Cited by 33 publications

References 30 publications

The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss

The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Shunts, channels and lipoprotein endosomal traffic: a new model of cholesterol homeostasis in the hepatocyte

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