The Experts below are selected from a list of 27567 Experts worldwide ranked by ideXlab platform
Richard A Rippe - One of the best experts on this subject based on the ideXlab platform.
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the role of p70s6k in Hepatic Stellate Cell collagen gene expression and Cell proliferation
Journal of Biological Chemistry, 2005Co-Authors: Erwin Gabele, David A. Brenner, Laura W Schrum, Shimon Reif, Shigeki Tsukada, Ramon Bataller, Yutaka Yata, Terry Morris, Richard A RippeAbstract:During fibrosis the Hepatic Stellate Cell (HSC) undergoes a complex activation process characterized by increased proliferation and extraCellular matrix deposition. The 70-kDa ribosomal S6 kinase (p70S6K) is activated by mitogens, growth factors, and hormones in a phosphatidylinositol 3-kinase-dependent manner. p70S6K regulates protein synthesis, proliferation, and Cell cycle control. Because these processes are involved in HSC activation, we investigated the role of p70S6K in HSC proliferation, Cell cycle control, and type I collagen expression. Platelet-derived growth factor (PDGF) stimulated p70S6K phosphorylation, which was blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase. Rapamycin blocked phosphorylation of p70S6K but had no affect on PDGF-induced Akt phosphorylation, positioning p70S6K downstream of Akt. Transforming growth factor-beta, which inhibits HSC proliferation, did not affect PDGF-induced p70S6K phosphorylation. Rapamycin treatment did not affect alpha1(I) collagen mRNA but reduced type I collagen protein secretion. Expression of smooth muscle alpha-actin was not affected by rapamycin treatment, indicating that HSC activation was not altered. Rapamycin inhibited serum-induced DNA synthesis approximately 2-fold. Moreover, rapamycin decreased expression of cyclins D1, D3, and E but not cyclin D2, Rb-Ser780, and Rb-Ser795. Together, p70S6K plays a crucial role in HSC proliferation, collagen expression, and Cell cycle control, thus representing a potential therapeutic target for liver fibrosis.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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liver fibrosis signals leading to the amplification of the fibrogenic Hepatic Stellate Cell
Frontiers in Bioscience, 2003Co-Authors: Erwin Gabele, David A. Brenner, Richard A RippeAbstract:Abstract Liver fibrosis represents a major medical problem with significant morbidity and mortality. Worldwide hepatitis viral infections represent the major cause liver fibrosis; however, within the United States chronic ethanol consumption is the leading cause of Hepatic fibrosis. Other known stimuli for liver fibrosis include helminthic infection, iron or copper overload and biliary obstruction. Fibrosis can be classified as a wound healing response to a variety of chronic stimuli that is characterized by an excessive deposition of extraCellular matrix proteins of which type I collagen predominates. This excess deposition of extraCellular matrix proteins disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ. If left untreated fibrosis can progress to liver cirrhosis ultimately leading to organ failure and death if left untreated. This review will discuss the molecular events leading to liver fibrosis. The discussion will include collagen gene regulation and proliferative signals that contribute to the amplification of the Hepatic Stellate Cell, the primary fibrogenic Cell type that resides in the liver.
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the role of smad3 in mediating mouse Hepatic Stellate Cell activation
Hepatology, 2001Co-Authors: Bernd Schnabl, Richard A Rippe, Young Oh Kweon, Joshua P Frederick, Xiaofan Wang, David A. BrennerAbstract:Transforming growth factor beta (TGF-beta) is the most potent profibrogenic mediator in liver fibrosis. Although Smad proteins have been identified as intraCellular mediators in the TGF-beta signaling pathway, the function of individual Smad proteins remains poorly understood. The aim of this study was to explore the contribution of Smad3 in mediating TGF-beta responses in a model of acute liver injury in vivo and in culture-activated Hepatic Stellate Cells (HSCs). Wild-type, Smad3 heterozygous or Smad3 homozygous knockout mice were treated with a single intragastric administration of CCl(4). After 72 hours, the induction of Hepatic collagen alpha1(I) and alpha2(I) messenger RNA (mRNA) levels in Smad3 knockout mice was only 42% and 64%, respectively, of the levels induced in wild-type mice. However, smooth muscle alpha-actin (alpha-SMA) was expressed at a slightly higher level in livers from knockout mice compared with wild-type mice. In culture-activated HSCs from Smad3 knockout mice, collagen alpha1(I) mRNA was 73% of wild-type HSCs, but alpha-SMA expression was the same. HSCs from knockout mice showed a higher proliferation rate than wild-type HSCs. Smad3-deficient HSCs did not form TGF-beta1-induced Smad-containing DNA-binding complexes. In conclusion, (1) maximal expression of collagen type I in activated HSCs requires Smad3 in vivo and in culture; (2) Smad3 is not necessary for HSC activation as assessed by alpha-SMA expression; (3) Smad3 is necessary for inhibition of proliferation of HSCs, which might be TGF-beta-dependent; and (4) Smad3 is required for TGF-beta1-mediated Smad-containing DNA-binding complex formation in cultured HSCs.
Hidekazu Tsukamoto - One of the best experts on this subject based on the ideXlab platform.
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morphogens and Hepatic Stellate Cell fate regulation in chronic liver disease
Journal of Gastroenterology and Hepatology, 2012Co-Authors: Hidekazu Tsukamoto, Jiaohong Wang, Kinji Asahina, Nianling Zhu, Keigo MachidaAbstract:Hepatic Stellate Cells (HSC) are the liver mesenchymal Cell type which responds to hepatoCellular damage and participates in wound healing. Although HSC myofibroblastic trans-differentiation (activation) is implicated in excessive extraCellular matrix deposition, molecular understanding of this phenotypic switch from the viewpoint of Cell fate regulation is limited. Recent studies demonstrate the roles of anti-adipogenic morphogens (Wnt, Necdin, Shh) in epigenetic repression of the HSC differentiation gene Pparγ as a causal event in HSC activation. These morphogens have positive cross-interactions which converge to epigenetic repression of Pparγ involving the methyl-CpG binding protein MeCP2. However, these morphogens expressed by activated HSC may also participate in cross-talk between HSC and hepatoblasts/hepatocytes to support liver regeneration, and their aberrant regulation may contribute to liver tumorigenesis. Implications of HSC-derived morphogens in these possibilities are discussed.
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wnt antagonism inhibits Hepatic Stellate Cell activation and liver fibrosis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2008Co-Authors: Jason H Cheng, Shigang Xiong, Hongyun She, Yuanping Han, Jiaohong Wang, Kinji Asahina, Hidekazu TsukamotoAbstract:Activation of Hepatic Stellate Cells (HSC), a key event in liver fibrosis, is caused by diminished adipogenic transcription. This study investigated whether Wnt signaling contributes to “antiadipog...
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peroxisome proliferator activated receptors and Hepatic Stellate Cell activation
Journal of Biological Chemistry, 2000Co-Authors: Takeo Miyahara, Richard A Rippe, Laura W Schrum, Shigang Xiong, Kenta Motomura, Frank A Anania, Timothy M Willson, Hidekazu TsukamotoAbstract:Abstract The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of Hepatic Stellate Cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPARγ1 but not that for the adipocyte-specific γ2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptase-polymerase chain reaction confirmed a 70% reduction in PPARγ mRNA level in HSC from BDL. Nuclear extracts from BDL Cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-κB and AP-1 binding were increased. Treatment of cultured-activated HSC with ligands for PPARγ (10 μm15-deoxy-Δ12,14-PGJ2 (15dPGJ2); 0.1∼10 μm BRL49653) inhibited DNA and collagen synthesis without affecting the Cell viability. Suppression of HSC collagen by 15dPGJ2 was abrogated 70% by the concomitant treatment with a PPARγ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPARα and γ (>100 μm) but not at those that only activate PPARα (<10 μm) or by a synthetic PPARα-selective agonist (GW9578). 15dPGJ2 reduced α1(I) procollagen, smooth muscle α-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ2 and BRL49653 inhibited α1(I) procollagen promoter activity. Tumor necrosis factor α (10 ng/ml) reduced PPARγ mRNA, and this effect was prevented by the treatment with 15dPGJ2. These results demonstrate that HSC activation is associated with the reductions in PPARγ expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPARγ ligands in vitro. These findings implicate diminished PPARγ signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPARγ ligands for liver fibrosis.
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peroxisome proliferator activated receptors and Hepatic Stellate Cell activation
Journal of Biological Chemistry, 2000Co-Authors: Takeo Miyahara, Richard A Rippe, Laura W Schrum, Shigang Xiong, Kenta Motomura, Frank A Anania, Timothy M Willson, Hal F Yee, Hidekazu TsukamotoAbstract:The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of Hepatic Stellate Cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPARgamma1 but not that for the adipocyte-specific gamma2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptase-polymerase chain reaction confirmed a 70% reduction in PPARgamma mRNA level in HSC from BDL. Nuclear extracts from BDL Cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-kappaB and AP-1 binding were increased. Treatment of cultured-activated HSC with ligands for PPARgamma (10 microm 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)); 0.1 approximately 10 microm BRL49653) inhibited DNA and collagen synthesis without affecting the Cell viability. Suppression of HSC collagen by 15dPGJ(2) was abrogated 70% by the concomitant treatment with a PPARgamma antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPARalpha and gamma (>100 microm) but not at those that only activate PPARalpha (<10 microm) or by a synthetic PPARalpha-selective agonist (GW9578). 15dPGJ(2) reduced alpha1(I) procollagen, smooth muscle alpha-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ(2) and BRL49653 inhibited alpha1(I) procollagen promoter activity. Tumor necrosis factor alpha (10 ng/ml) reduced PPARgamma mRNA, and this effect was prevented by the treatment with 15dPGJ(2). These results demonstrate that HSC activation is associated with the reductions in PPARgamma expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPARgamma ligands in vitro. These findings implicate diminished PPARgamma signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPARgamma ligands for liver fibrosis.
Elmar R Burchardt - One of the best experts on this subject based on the ideXlab platform.
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the role of tgfβ1 in initiating Hepatic Stellate Cell activation in vivo
Journal of Hepatology, 1999Co-Authors: C Hellerbrand, Branko Stefanovic, Frank Giordano, Elmar R BurchardtAbstract:Abstract Background/Aims: The activation of Hepatic Stellate Cells is a key initiating event in Hepatic fibrogenesis. Although TGFβ1 is a potent inducer of collagen α1(I) expression in vitro and elevated levels of TGFβ1 are found in patients and experimental animals with Hepatic fibrosis and cirrhosis, the role of increased TGFβ1 in the initiation of Hepatic Stellate Cell activation in vivo is unknown. We used two experimental approaches to study this relationship: 1) Induction of an acute liver injury with carbon tetrachloride (CCl 4 ) in normal and TGFβ1-knockout (ko) mice, and 2) overexpression of TGFβ1 in the liver of wild-type mice using a recombinant replication-deficient adenovirus encoding human TGFβ1 (Ad-TGFβ1). Methods: TGFβ1-ko mice ( n =6) and normal mice ( n =6) were injected once intraperitoneally (ip) with CCl 4 (1 μl/g BW) or mineral oil. Wild-type mice ( n =3) were injected intravenously with Ad-TGFβ1 (10 10 pfu) or a control virus expressing β-galactosidase (Ad-LacZ, 10 10 pfu). Animals were sacrificed after 3 days and total liver RNA was prepared. The expression of collagen α1(I) mRNA normalized to GAPDH mRNA was measured by RNase protection assay, α-smooth muscle actin (α-sma) protein expression was analyzed by Western blotting. The expression of TGFβ1, TGFβ2, and TGFβ3 mRNAs were determined semi-quantitatively with RT-PCR. Results: The collagen α1(I) mRNA was increased 10-fold in CCl 4 -treated wild-type mice compared to the controls. This increase was reduced about 80% in the TGFβ1-ko mice. The TGFβ1 mRNA levels in the wild-type mice were proportional to the collagen α1(I) mRNA levels. α-sma, a marker of Hepatic Stellate Cell activation, was expressed earlier and at a higher level in wild-type mice than TGFβ-ko mice after CCl 4 treatment. The Ad-TGFβ1 infected mice had 14-fold higher Hepatic TGFβ protein levels and 15-fold higher collagen α1(I) mRNA levels than the Ad-LacZ-infected control mice. Collagen α1(I) mRNA levels were proportional to the transgenic TGFβ1 mRNA levels, while the endogenous TGFβ1 was only slightly higher than in the controls. TGFβ2 and TGFβ3 mRNA levels were elevated in CCl 4 -treated wild-type and TGFβ1-ko mice and in Ad-TGFβ1-infected mice compared to the controls. Conclusions: Absence of TGFβ1 inhibits Hepatic collagen α1(I) mRNA and α-sma protein expression by the toxic stimulus CCl 4 , and targeted TGFβ1 overexpression increases collagen α1(I) mRNA and α-sma protein levels in the liver in vivo. Other TGFβ family members do not compensate for the TGFβ1 deficiency. This indicates that TGFβ1 accelerates, but is not absolutely required, for the activation of Hepatic Stellate Cells.
David A. Brenner - One of the best experts on this subject based on the ideXlab platform.
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the role of p70s6k in Hepatic Stellate Cell collagen gene expression and Cell proliferation
Journal of Biological Chemistry, 2005Co-Authors: Erwin Gabele, David A. Brenner, Laura W Schrum, Shimon Reif, Shigeki Tsukada, Ramon Bataller, Yutaka Yata, Terry Morris, Richard A RippeAbstract:During fibrosis the Hepatic Stellate Cell (HSC) undergoes a complex activation process characterized by increased proliferation and extraCellular matrix deposition. The 70-kDa ribosomal S6 kinase (p70S6K) is activated by mitogens, growth factors, and hormones in a phosphatidylinositol 3-kinase-dependent manner. p70S6K regulates protein synthesis, proliferation, and Cell cycle control. Because these processes are involved in HSC activation, we investigated the role of p70S6K in HSC proliferation, Cell cycle control, and type I collagen expression. Platelet-derived growth factor (PDGF) stimulated p70S6K phosphorylation, which was blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase. Rapamycin blocked phosphorylation of p70S6K but had no affect on PDGF-induced Akt phosphorylation, positioning p70S6K downstream of Akt. Transforming growth factor-beta, which inhibits HSC proliferation, did not affect PDGF-induced p70S6K phosphorylation. Rapamycin treatment did not affect alpha1(I) collagen mRNA but reduced type I collagen protein secretion. Expression of smooth muscle alpha-actin was not affected by rapamycin treatment, indicating that HSC activation was not altered. Rapamycin inhibited serum-induced DNA synthesis approximately 2-fold. Moreover, rapamycin decreased expression of cyclins D1, D3, and E but not cyclin D2, Rb-Ser780, and Rb-Ser795. Together, p70S6K plays a crucial role in HSC proliferation, collagen expression, and Cell cycle control, thus representing a potential therapeutic target for liver fibrosis.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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liver fibrosis signals leading to the amplification of the fibrogenic Hepatic Stellate Cell
Frontiers in Bioscience, 2003Co-Authors: Erwin Gabele, David A. Brenner, Richard A RippeAbstract:Abstract Liver fibrosis represents a major medical problem with significant morbidity and mortality. Worldwide hepatitis viral infections represent the major cause liver fibrosis; however, within the United States chronic ethanol consumption is the leading cause of Hepatic fibrosis. Other known stimuli for liver fibrosis include helminthic infection, iron or copper overload and biliary obstruction. Fibrosis can be classified as a wound healing response to a variety of chronic stimuli that is characterized by an excessive deposition of extraCellular matrix proteins of which type I collagen predominates. This excess deposition of extraCellular matrix proteins disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ. If left untreated fibrosis can progress to liver cirrhosis ultimately leading to organ failure and death if left untreated. This review will discuss the molecular events leading to liver fibrosis. The discussion will include collagen gene regulation and proliferative signals that contribute to the amplification of the Hepatic Stellate Cell, the primary fibrogenic Cell type that resides in the liver.
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the role of smad3 in mediating mouse Hepatic Stellate Cell activation
Hepatology, 2001Co-Authors: Bernd Schnabl, Richard A Rippe, Young Oh Kweon, Joshua P Frederick, Xiaofan Wang, David A. BrennerAbstract:Transforming growth factor beta (TGF-beta) is the most potent profibrogenic mediator in liver fibrosis. Although Smad proteins have been identified as intraCellular mediators in the TGF-beta signaling pathway, the function of individual Smad proteins remains poorly understood. The aim of this study was to explore the contribution of Smad3 in mediating TGF-beta responses in a model of acute liver injury in vivo and in culture-activated Hepatic Stellate Cells (HSCs). Wild-type, Smad3 heterozygous or Smad3 homozygous knockout mice were treated with a single intragastric administration of CCl(4). After 72 hours, the induction of Hepatic collagen alpha1(I) and alpha2(I) messenger RNA (mRNA) levels in Smad3 knockout mice was only 42% and 64%, respectively, of the levels induced in wild-type mice. However, smooth muscle alpha-actin (alpha-SMA) was expressed at a slightly higher level in livers from knockout mice compared with wild-type mice. In culture-activated HSCs from Smad3 knockout mice, collagen alpha1(I) mRNA was 73% of wild-type HSCs, but alpha-SMA expression was the same. HSCs from knockout mice showed a higher proliferation rate than wild-type HSCs. Smad3-deficient HSCs did not form TGF-beta1-induced Smad-containing DNA-binding complexes. In conclusion, (1) maximal expression of collagen type I in activated HSCs requires Smad3 in vivo and in culture; (2) Smad3 is not necessary for HSC activation as assessed by alpha-SMA expression; (3) Smad3 is necessary for inhibition of proliferation of HSCs, which might be TGF-beta-dependent; and (4) Smad3 is required for TGF-beta1-mediated Smad-containing DNA-binding complex formation in cultured HSCs.
Erwin Gabele - One of the best experts on this subject based on the ideXlab platform.
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the role of p70s6k in Hepatic Stellate Cell collagen gene expression and Cell proliferation
Journal of Biological Chemistry, 2005Co-Authors: Erwin Gabele, David A. Brenner, Laura W Schrum, Shimon Reif, Shigeki Tsukada, Ramon Bataller, Yutaka Yata, Terry Morris, Richard A RippeAbstract:During fibrosis the Hepatic Stellate Cell (HSC) undergoes a complex activation process characterized by increased proliferation and extraCellular matrix deposition. The 70-kDa ribosomal S6 kinase (p70S6K) is activated by mitogens, growth factors, and hormones in a phosphatidylinositol 3-kinase-dependent manner. p70S6K regulates protein synthesis, proliferation, and Cell cycle control. Because these processes are involved in HSC activation, we investigated the role of p70S6K in HSC proliferation, Cell cycle control, and type I collagen expression. Platelet-derived growth factor (PDGF) stimulated p70S6K phosphorylation, which was blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase. Rapamycin blocked phosphorylation of p70S6K but had no affect on PDGF-induced Akt phosphorylation, positioning p70S6K downstream of Akt. Transforming growth factor-beta, which inhibits HSC proliferation, did not affect PDGF-induced p70S6K phosphorylation. Rapamycin treatment did not affect alpha1(I) collagen mRNA but reduced type I collagen protein secretion. Expression of smooth muscle alpha-actin was not affected by rapamycin treatment, indicating that HSC activation was not altered. Rapamycin inhibited serum-induced DNA synthesis approximately 2-fold. Moreover, rapamycin decreased expression of cyclins D1, D3, and E but not cyclin D2, Rb-Ser780, and Rb-Ser795. Together, p70S6K plays a crucial role in HSC proliferation, collagen expression, and Cell cycle control, thus representing a potential therapeutic target for liver fibrosis.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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the role of focal adhesion kinase phosphatidylinositol 3 kinase akt signaling in Hepatic Stellate Cell proliferation and type i collagen expression
Journal of Biological Chemistry, 2003Co-Authors: Shimon Reif, David A. Brenner, Erwin Gabele, Yutaka Yata, Alon Lang, Jeffery N Lindquist, Andrew Scanga, Richard A RippeAbstract:Abstract Following a fibrogenic stimulus, the Hepatic Stellate Cell (HSC) undergoes a complex activation process associated with increased Cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several Cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, Cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, Cell attachment, and PDGF-induced Cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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liver fibrosis signals leading to the amplification of the fibrogenic Hepatic Stellate Cell
Frontiers in Bioscience, 2003Co-Authors: Erwin Gabele, David A. Brenner, Richard A RippeAbstract:Abstract Liver fibrosis represents a major medical problem with significant morbidity and mortality. Worldwide hepatitis viral infections represent the major cause liver fibrosis; however, within the United States chronic ethanol consumption is the leading cause of Hepatic fibrosis. Other known stimuli for liver fibrosis include helminthic infection, iron or copper overload and biliary obstruction. Fibrosis can be classified as a wound healing response to a variety of chronic stimuli that is characterized by an excessive deposition of extraCellular matrix proteins of which type I collagen predominates. This excess deposition of extraCellular matrix proteins disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ. If left untreated fibrosis can progress to liver cirrhosis ultimately leading to organ failure and death if left untreated. This review will discuss the molecular events leading to liver fibrosis. The discussion will include collagen gene regulation and proliferative signals that contribute to the amplification of the Hepatic Stellate Cell, the primary fibrogenic Cell type that resides in the liver.