التفاصيل البيبلوغرافية
| العنوان: |
RhoA/ROCK I signalling downstream of the P2Y13 ADP-receptor controls HDL endocytosis in human hepatocytes |
| المؤلفون: |
Malaval, Camille, Laffargue, Muriel, Barbaras, Ronald, Rolland, Corinne, Peres, Christine, Champagne, Eric, Perret, Bertrand, Tercé, François, Collet, Xavier, Martinez, Laurent O. laurent.martinez@inserm.fr |
| المصدر: |
Cellular Signalling. Jan2009, Vol. 21 Issue 1, p120-127. 8p. |
| مصطلحات موضوعية: |
*GUANOSINE triphosphatase, *CELLULAR signal transduction, *PURINERGIC receptors, *HIGH density lipoproteins, *ENDOCYTOSIS, *LIVER cells |
| مستخلص: |
Abstract: Cell surface receptors for high-density lipoprotein (HDL) on hepatocytes are major partners in the regulation of cholesterol homeostasis. We have previously demonstrated on human hepatocytes that apolipoprotein A-I binding to an ectopic F1-ATPase stimulates the production of extracellular ADP that activates a P2Y13-mediated high-density lipoprotein (HDL) endocytosis pathway. However, P2Y13-dependent signalling pathway has never been described yet. The current study demonstrates a major role of cytoskeleton reorganization in F1-ATPase/P2Y13-dependent HDL endocytosis under the control of the small GTPase RhoA and its effector ROCK I. Indeed human hepatocytes (HepG2 cells) stimulated by ADP or AR-C69931MX (both P2Y13 agonists) showed a high specific activation of RhoA; in addition, inhibition of Rho proteins by C3 exoenzyme impairs HDL endocytosis whereas a constitutively active form of RhoA stimulates HDL endocytosis at the same level as under F1-ATPase/P2Y13 activation. Pharmacological inhibition of ROCK activity decreased HDL endocytosis following stimulation by apoA-I (F1-ATPase ligand), ADP or AR-C69931MX and specific siRNA ROCK I extinction prevented the stimulation of HDL endocytosis without effect of ROCK II extinction. The functional involvement of ROCK I downstream F1-ATPase/P2Y13 was confirmed by the strong enrichment of the membrane fraction in ROCK I and by the requirement of actin polymerization in hepatocyte HDL endocytosis. These results allow the identification of the molecular events downstream P2Y13 receptor activation for a better understanding of hepatocyte HDL endocytosis, the latest step in reverse cholesterol transport. [Copyright &y& Elsevier] |
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