Role of Rho small GTP binding protein in the regulation of actin cytoskeleton in hepatic stellate cells

Kato, Masaki; Iwamoto, Hiroaki; Higashi, Nobuhiko; Sugimoto, Rie; Uchimura, Koutaro; Tada, Seiya; Sakai, Hironori; Nakamuta, Makoto; Nawata, Hajime

doi:10.1016/s0168-8278(99)80168-8

Cited by 43 publications

(34 citation statements)

References 38 publications

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“…We also observed induction of RhoB, which regulates signal transduction from plasma membrane receptors (45,46). RhoB is known also to regulate DNA synthesis and is expressed as a result of genotoxic stress (47).…”

Section: Extracellular Matrix͞cell Structure-and Membrane-associated mentioning

confidence: 71%

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

Guidotti

Pezacki

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

189

181

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Section: Extracellular Matrix͞cell Structure-and Membrane-associated mentioning

confidence: 71%

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

Guidotti

Pezacki

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

189

181

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“…2,4,5 In vitro-activated HSC have also been demonstrated to change their morphology with loss of lipid droplets and increased expression of a-SMA. [32][33][34] In our previous study, prophylactic treatment starting directly after the BDL resulted in a lower number of MFB in the liver and less collagen accumulation, but without significant decrease in cytokine production or inflammation. 8 If atorvastatin was administrated later, but still before established fibrosis, collagen formation was reduced.…”

Section: Discussionmentioning

confidence: 83%

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Klein

Klösel

Schierwagen

et al. 2012

Laboratory Investigation

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Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile ductligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10 À 4 , 10 À 5 and 10 À 6 M), transcription levels of profibrotic cytokines (transforming growth factor-b1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. a-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and b-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10 À 4 M and attenuated it at 10 À 5 M. Atorvastatin induced p21 protein expression and b-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells.

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“…Because MHC gene products are critical in regulating antiviral immune reactions against both HBV and HCV, genetic factors controlling the host's immune response might also play an important role in determining the disease severity in patients with viral hepatitis [28][29][30] . In addition, we identified several genes, such as PIK3C2B and ARHGDIB, which regulate the activation of hepatic stellate cells [31,32] , which might contribute to the molecular pathogenesis of liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease

Utsunomiya

Okamoto

Wakiyama

et al. 2007

WJG

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AIM:To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease. METHODS:Using a cDNA microarray containing over 22 000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azanstained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis. RESULTS:We identified 39 genes that collectively showed a good correlation (r > 0.50) between geneexpression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis, we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r = 0.76, 2.2% vs 2.8%, P < 0.0001) and 12 independent additional test samples (r = 0.75, 9.8% vs 8.6%, P < 0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r = -0.53), type Ⅳ collagen 7s (r = 0.48), hyaluronic acid (r = 0.41), and aspartate aminotransferase to platelets ratio index (APRI) (r = 0.38). CONCLUSION:Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

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Role of Rho small GTP binding protein in the regulation of actin cytoskeleton in hepatic stellate cells

Cited by 43 publications

References 38 publications

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

Gene expression during the priming phase of liver regeneration after partial hepatectomy in mice

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

A specific gene-expression signature quantifies the degree of hepatic fibrosis in patients with chronic liver disease

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