4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells

Zamara, E.; Novo, Erica; Marra, Fabio; Gentilini, Alessandra; Romanelli, Roberto Giulio; Caligiuri, Alessandra; Robino, Gaia; Tamagno, Elena; Aragno, Manuela; Danni, Oliviero; Autelli, Riccardo; Colombatto, Sebastiano; Dianzani, Mario U.; Pinzani, Massimo; Parola, Maurizio

doi:10.1016/s0168-8278(03)00480-x

Cited by 105 publications

(100 citation statements)

References 52 publications

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“…Acute liver injury was induced by single oral treatment with carbon tetrachloride (CCl 4 ) and animals were sacrificed from 24 to 96 h, as previously described [16].…”

Section: Animal Experimentsmentioning

confidence: 99%

Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells

Novo

Busletta

Bonzo

et al. 2011

Journal of Hepatology

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110

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“…Acute liver injury was induced by single oral treatment with carbon tetrachloride (CCl 4 ) and animals were sacrificed from 24 to 96 h, as previously described [16].…”

Section: Animal Experimentsmentioning

confidence: 99%

Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells

Novo

Busletta

Bonzo

et al. 2011

Journal of Hepatology

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110

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“…In addition, Ren2 rats exhibit increased liver 4-HNE levels (Fig. 4) which is known to activate hepatic stellate cells and enhance procollagen expression [38]. These factors may have contributed to the development of rapid and more severe liver fibrosis in the Ren2 rat model (Fig.…”

mentioning

confidence: 99%

Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats

Wei

Clark

Morris

et al. 2008

Journal of Hepatology

104

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Background/Aims-Non-alcoholic fatty liver disease (NAFLD) is a common health problem and includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. The renin-angiotensin system (RAS) plays a vital role in blood pressure regulation and appears to promote hepatic fibrogenesis. We hypothesized that increased RAS activity causes NAFLD due to increased hepatic oxidative stress.Methods-We employed the transgenic TG(mRen2)27(Ren2) hypertensive rat, harboring the mouse renin gene with elevated tissue Angiotensin II (Ang II).Results-Compared with normotensive Sprague-Dawley (SD) control rats, Ren2 developed significant hepatic steatosis by 9 weeks of age that progressed to marked steatohepatitis and fibrosis by 12 weeks. These changes were associated with increased levels of hepatic reactive oxygen species (ROS) and lipid peroxidation. Accordingly, 9-week-old Ren2 rats were treated for 3 weeks with valsartan, an angiotensin type 1 receptor blocker, or tempol, a superoxide dismutase/catalase mimetic. Hepatic indices for oxidative stress, steatosis, inflammation and fibrosis were markedly attenuated by both valsartan and tempol treatment.Conclusions-This study suggests that Ang II causes development and progression of NAFLD in the transgenic Ren2 rat model by increasing hepatic ROS. Our findings also support a potential role of RAS in prevention and treatment of NAFLD.

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“…Finally, 4-hydroxynonenal added to cultured HSC upregulates the synthesis of procollagen a1 (I). 11 Despite the many studies carried out on oxidative stress, there has not been a reliable and noninvasive method to monitor lipid peroxidation in vivo, as with the use of blood and urine. Some years ago, however, the group of Morrow et al 12 demonstrated the production of a series of prostaglandin F 2 -like compounds, named F 2 -isoprostanes, which are formed in vivo and in vitro by free radical-catalyzed peroxidation of phospholipid-bound arachidonic acid, 13 a pathway that is independent of the cyclooxygenase pathway.…”

mentioning

confidence: 99%

“…F 2 -isoprostanes might therefore be considered a reliable marker of oxidative stress (lipid peroxidation) 14 and thus be used to evaluate the oxidative status in a number of human pathologies, such as alcoholic liver disease and diabetes. 15 Since aldehydic lipid peroxidation products, like 4-hydroxynonenal, have been reported [8][9][10][11] to induce collagen expression and synthesis, we have investigated whether analogous effects can be obtained with F 2 -isoprostanes, the most proximal derivatives of peroxidizing arachidonic acid. One potential advantage of isoprostanes over aldehydes is that while aldehydes can interact with cellular macromolecules by addition processes only, isoprostanes could possess receptors able to induce specific signal transduction pathways.…”

mentioning

confidence: 99%

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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Carbon tetrachloride (CCl 4 )-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F 2 -isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F 2 -isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl 4 -induced hepatic fibrosis, plasma F 2 -isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F 2 -isoprostanes in the concentration range found in the in vivo studies (10 À9 -10 À8 M), a striking increase in DNA synthesis (reversed by the thromboxane A 2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F 2 -isoprostanes markedly increased the production of transforming growth factor-b1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F 2 -isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.

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4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells

Cited by 105 publications

References 52 publications

Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells

Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells

Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

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