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01.08.2014 | Original Article

The Role of Phospholipase D1 in Liver Fibrosis Induced by Dimethylnitrosamine In Vivo

verfasst von: Xinyan Zhu, Ruilin Liu, Dapeng Kuang, Jingqi Liu, Xiaomeng Shi, Tingting Zhang, Yu Zeng, Xianghua Sun, Yi Zhang, Wenzhuo Yang

Erschienen in: Digestive Diseases and Sciences | Ausgabe 8/2014

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Abstract

Background

Phospholipase D (PLD) has been proved to be involved in regulating function of fibroblasts and might play a role in mediating organic fibrosis.

Aims

To investigate the role and mechanism of PLD on dimethylnitrosamine (DMN)-induced rat liver fibrosis.

Methods

Fifty-five male Wistar rats were divided into normal control group, DMN model group, N-methylethanolamine (MEA) control group, and MEA-intervention group. We observed the effects of MEA, a PLD inhibitor on the development and progression of rat liver fibrosis by comparing the physical and biochemical indexes, tissue pathology, PLD activity, and typical markers and cytokines related to fibrosis in the four groups.

Results

Accompanied by the down-regulation of PLD1 expression, the MEA-intervention group had improved outcomes compared with the DMN model group in terms of spleen weight, spleen/weight index, serum and tissue biochemical indexes, tissue hydroxyproline, and tissue pathology. The MEA-intervention group had lower TIMP1, COL1A1, and higher MMPs expression level than the DMN model group. The activity of PLD and PLD1, α-SMA expression level in the MEA-intervention group was much lower than those in the DMN model group. There was no significant difference between the two groups in the expression level of TGF-β1 and MCP1. Meanwhile, there were no significant differences between normal control group and MEA control group in the parameters stated above.

Conclusion

Phospholipase D1 may play an important role in the development and progression of rat liver fibrosis. Inhibition of PLD may become a new strategy to prevent or alleviate liver fibrosis.

Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669.PubMedCentralPubMedCrossRef

McDermott M, Wakelam MJ, Morris AJ. Phospholipase D. Biochem Cell Biol. 2004;82:225–253.PubMedCrossRef

Liscovitch M, Czarny M, Fiucci G, et al. Phospholipase D: molecular and cell biology of a novel gene family. Biochem J. 2000;345:401–415.PubMedCentralPubMedCrossRef

Exton JH. Phospholipase D-structure, regulation and function. Rev Physiol Biochem Pharmacol. 2002;144:1–94.PubMedCrossRef

Jenkins GM, Frohman MA. Phospholipase D a lipid centric review. Cell Mol Life Sci. 2005;62:2305–2316.PubMedCrossRef

Roth MG. Molecular mechanisms of PLD function in membrane traffic. Traffic. 2008;9:1233–1239.PubMedCrossRef

Komati H, Naro F, Mebarek S, et al. Phospholipase D is involved in myogenic differentiation through remodeling of actin cytoskeleton. Mol Biol Cell. 2005;16:1232–1244.PubMedCentralPubMedCrossRef

Rudge SA, Wakelam MJ. Inter-regulatory dynamics of phospholipase D and the actin cytoskeleton. Biochim Biophys Acta. 2009;1791:856–861.PubMedCrossRef

Chae YC, Kim JH, Kim KL, et al. Phospholipase D activity regulates integrin-mediated cell spreading and migration by inducing GTP-Rac translocation to the plasma membrane. Mol Biol Cell. 2008;19:3111–3123.PubMedCentralPubMedCrossRef

10.

Horstmeyer A, Licht C, Scherr G, et al. Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. FEBS J. 2005;272:6297–6309.PubMedCrossRef

11.

Andersson L, Bostrom P, Ericson J, et al. PLD1 and ERK2 regulate cytosolic lipid droplet formation. J Cell Sci. 2006;119:2246–2257.PubMedCrossRef

12.

Marchesan D, Rutberg M, Andersson L, et al. A phospholipase D-dependent process forms lipid droplets containing caveolin, adipocyte differentiation-related protein, and vimentin in a cell-free system. J Biol Chem. 2003;278:27293–27300.PubMedCrossRef

13.

Lee S, Park JB, Kim JH, et al. Actin directly interacts with phospholipase D, inhibiting its activity. J Biol Chem. 2001;276:28252–28260.PubMedCrossRef

14.

Kam Y, Exton JH. Phospholipase D activity is required for actin stress fiber formation in fibroblasts. Mol Cell Biol. 2001;21:4055–4066.PubMedCentralPubMedCrossRef

15.

Pilquil C, Dewald J, Cherney A, et al. Lipid phosphate phosphatase-1 regulates lysophosphatidate-induced fibroblast migration by controlling phospholipase D2-dependent phosphatidate generation. J Biol Chem. 2006;281:38418–38429.PubMedCrossRef

16.

Yamamoto K, Takahashi Y, Mano T, et al. N-methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism. Eur Heart J. 2004;25:1221–1229.PubMedCrossRef

17.

Baroni GS, D’Ambrosio L, Curto P, et al. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology. 1996;23:1189–1199.PubMedCrossRef

18.

Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000;31:241–246.PubMedCrossRef

19.

Itoh S, ten Dijke P. Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol. 2007;19:176–184.PubMedCrossRef

20.

Hu P-F, Zhu Y-W, Zhong W, et al. Inhibition of plasminogen activator inhibitor-1 expression by siRNA in rat hepatic stellate cells. J Gastroenterol Hepatol. 2008;23:1917–1925.PubMedCrossRef

21.

Trebicka J, Racz I, Siegmund SV, et al. Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB2 receptor-deficient mice and decreased in CB1 receptor knockouts. Liver Int. 2011;31:860–870.PubMedCrossRef

22.

Benitez-Rajal J, Lorite MJ, Burt AD, et al. Phospholipase D and extracellular signal-regulated kinase in hepatic stellate cells: effects of platelet-derived growth factor and extracellular nucleotides. Am J Physiol Gastrointest Liver Physiol. 2006;291:G977–G986.PubMedCrossRef

23.

Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324–1332.PubMedCrossRef

24.

Du G, Altshuller YM, Kim Y, et al. Dual requirement for rho and protein kinase C in direct activation of phospholipase D1 through G protein-coupled receptor signaling. Mol Biol Cell. 2000;11:4359–4368.PubMedCentralPubMedCrossRef

25.

Colley WC, Sung TC, Roll R, et al. Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr Biol. 1997;7:191–201.PubMedCrossRef

26.

Du G, Huang P, Liang BT, et al. Phospholipase D2 localizes to the plasma membrane and regulates angiotensin II receptor endocytosis. Mol Biol Cell. 2004;15:1024–1030.PubMedCentralPubMedCrossRef

27.

Freyberg Z, Sweeney D, Siddhanta A, et al. Intracellular localization of phospholipase D1 in mammalian cells. Mol Biol Cell. 2001;12:943–955.PubMedCentralPubMedCrossRef

28.

Noh DY, Ahn SJ, Lee RA, et al. Overexpression of phospholipase D1 in human breast cancer tissues. Cancer Lett. 2000;161:207–214.PubMedCrossRef

29.

Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–1113.PubMedCrossRef

30.

Saito M, Iwadate M, Higashimoto M, et al. Expression of phospholipase D2 in human colorectal carcinoma. Oncol Rep. 2007;18:1329–1334.PubMed

31.

Zhao Y, Ehara H, Akao Y, et al. Increased activity and intranuclear expression of phospholipase D2 in human renal cancer. Biochem Biophys Res Commun. 2000;278:140–143.PubMedCrossRef

32.

Cai D, Zhong M, Wang R, et al. Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer’s disease-linked presenilin-1 mutant neurons. Proc Natl Acad Sci USA. 2006;103:1936–1940.PubMedCentralPubMedCrossRef

33.

Gorbatyuk OS, Li S, Nha Nguyen F, et al. Alpha-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Mol Ther. 2010;18:1758–1768.

34.

Oliveira TG, Chan RB, Tian H, et al. Phospholipase d2 ablation ameliorates Alzheimer’s disease-linked synaptic dysfunction and cognitive deficits. J Neurosci. 2010;30:16419–16428.PubMedCentralPubMedCrossRef

35.

Zhang Y, Kanaho Y, Frohman MA, et al. Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth. J Neurosci. 2005;25:1797–1805.PubMedCrossRef

36.

Vorland M, Holmsen H. Phospholipase D in human platelets: presence of isoenzymes and participation of autocrine stimulation during thrombin activation. Platelets. 2008;19:211–224.PubMedCrossRef

37.

Vorland M, Holmsen H. Phospholipase D activity in human platelets is inhibited by protein kinase A, involving inhibition of phospholipase D1 translocation. Platelets. 2008;19:300–307.PubMedCrossRef

38.

Su W, Chen Q, Frohman MA. Targeting phospholipase D with small-molecule inhibitors as a potential therapeutic approach for cancer metastasis. Future Oncol. 2009;5:1477–1486.PubMedCentralPubMedCrossRef

39.

Elvers M, Stegner D, Hagedorn I, et al. Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci Signal. 2010;3:ra1.

40.

Hong KW, Jin HS, Lim JE, et al. Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension. J Hum Hypertens. 2010;24:763–774.PubMedCrossRef

41.

Tsukahara T, Tsukahara R, Fujiwara Y, et al. Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. Mol Cell. 2010;39:421–432.PubMedCentralPubMedCrossRef

42.

Disse J, Vitale N, Bader MF, et al. Phospholipase D1 is specifically required for regulated secretion of von Willebrand factor from endothelial cells. Blood. 2009;113:973–980.PubMedCrossRef

Titel: The Role of Phospholipase D1 in Liver Fibrosis Induced by Dimethylnitrosamine In Vivo
verfasst von: Xinyan Zhu
Ruilin Liu
Dapeng Kuang
Jingqi Liu
Xiaomeng Shi
Tingting Zhang
Yu Zeng
Xianghua Sun
Yi Zhang
Wenzhuo Yang
Publikationsdatum: 01.08.2014
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 8/2014
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-014-3130-6

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Abstract

Background

Aims

Methods

Results

Conclusion

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