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M1580 Loss of Hepatic Stellate Cell Lipid Droplets Does Not Contribute to Stellate Cell Activation and Liver Fibrosis
were treated with the mTOR1 inhibitor, rapamycin (5 nM). Results: Insulin increased the phosphorylation of Akt and p70-S6K, indicating activation of these molecules. The insulinmediated phosphorylation of p70-S6K was potentiated by leptin and was inhibited by rapamycin. HSC proliferation and collagen type I expression were also suppressed by rapamycin. SMA expression was not affected by insulin with or without leptin both in primary and fully activated HSC. Conclusions: Insulin increases the phosphorylation of Akt and p70S6K in both primary and fully activated HSC. Leptin potentiates these insulin-mediated signaling events. Phosphorylation of p70-S6K, cell proliferation and type I collagen expression are inhibited by rapamycin. Since hyperinsulinemia and elevated leptin are important clinical features of NASH, our results suggest that insulin and leptin may promote HSC activation both at the early and progressive stage. Insulin- and leptin-mediated signaling pathways may be potential therapeutic targets to inhibit liver fibrogenesis in NASH.
little, if any, Hh pathway activity has ever been detected in healthy adult liver. Our Aim was to determine if primary human hepatic stellate cells (hHSC) produce and/or respond to Hh ligands. Selected findings were corroborated in the human LX2 cell line. Methods: Primary hHSCs were obtained from healthy liver segments of 2 patients undergoing resection of metastases. RNA was harvested from freshly isolated hHSC, and from hHSC cultured for 2, 4, and 10 days. Myofibroblastic activation was verified by Q-RT-PCR analysis of peroxisome proliferator activated receptor(PPAR)γ, transforming growth factor (TGF)β1, plasminogen activator inhibitor (PAI)-1, α-smooth muscle actin (αSMA) and collagenIα1. Expression of Hh pathway ligands (sonic and indian hedgehog , shh and ihh), receptor (patched), coreceptor (smoothened), Hh-regulated target genes (gli1, gli2, gli3), as well the Hh inhibitor, Hedgehog interacting peptide (hip), were correlated with activation. Expression of these mRNAs was also assessed in LX2 cells. To investigate the effect of Hh signaling, caspase 3/ 7 activity was compared in LX2 cells treated with Hh-neutralizing antibodies or control IgG. Results: Primary hHSC expression of PPARγ fell by 80%, while TGFβ1, PAI-1, αSMA, and collagen respectively increased 4-, 2-, 140- and 400- fold during 10-day culture. During this time, expression of both Hh ligands doubled, Hip expression fell, and expression of 2 Hh target genes, Gli2 and Gli3, increased at least 2 fold. Cultured LX2 cells also expressed mRNAs for Hh pathway ligands, signaling components, and target genes. Treatment of LX2 cells with Hh-neutralizing antibodies increased caspase 3/7 activity (p < 0.05). Conclusion: Primary HSC from healthy human livers express Hh ligands, signaling components and target genes, and expression of these mRNAs increases as HSC become myofibroblastic. Moreover, inhibiting Hh signaling in myofibroblastic human HSC increases apoptosis. These findings suggest that Hh signaling occurs during remodeling of human adult livers.
M1580
AASLD Abstracts
Loss of Hepatic Stellate Cell Lipid Droplets Does Not Contribute to Stellate Cell Activation and Liver Fibrosis Johannes Kluwe, Nuttaporn Wongsiriroj, Roseann Zott, William S. Blaner, Robert F. Schwabe Background: Following liver injury, hepatic stellate cells (HSCs) undergo a well described activation process that transforms them from a vitamin A-storing to a myofibroblast-like cell type. One of the most striking features of this transformation is the gradual loss of vitamin A-containing lipid droplets which is not only considered a hallmark of activation but also an essential event that drives the HSC activation process. However, the exact contribution of lipid droplets to HSC activation and fibrogenesis remains largely unknown. Aim: To determine whether the absence of HSC lipid droplets promotes fibrogenesis in a genetic mouse model that lacks lipid droplets in HSCs. Methods: The role of lipid droplets in HSC activation and fibrogenesis was investigated in lecithin:retinol acyltransferase (LRAT)deficient mice which display an absence of hepatic retinyl esters and a complete lack of lipid droplets in HSCs. Experimental fibrogenesis was induced by ligation of the common bile duct (BDL) or by injection of either 1 or 8 doses of CCl4 (0.5 µl/g body weight). Spontaneous and experimental fibrosis was evaluated by Sirius red staining, αSMA protein content and mRNA levels of collagen α1(I), TIMP-1 and αSMA as determined by quantitative real time PCR. Results: LRAT-deficient mice did not display an increase in spontaneous fibrosis at the age of three months as determined by Sirius red staining and mRNA levels of collagen α1(I), TIMP-1 and αSMA. Interestingly, there was also no difference in the degree of liver fibrosis between wild-type and LRAT-deficient mice after 1 or 8 injections of CCl4 as judged by Sirius Red staining, αSMA western blot and mRNA levels for collagen α1(I) and TIMP-1. This data was further confirmed using BDL as a second model of experimental fibrogenesis. After 3 weeks of BDL, wild-type and LRAT-deficient mice displayed the same degree of liver fibrosis. Conclusion: The absence of increased spontaneous and experimental fibrosis in LRAT-deficient mice suggests that the loss of lipid droplets does not drive HSC activation and liver fibrosis. Thus, lipid/vitamin A storage and extracellular matrix synthesis are two important, yet unrelated functions of HSCs.
M1583 Inhibition of NADPH Oxidase Suppresses Fibrogenesis Ghazaleh Aram, James J. Potter, Xiaopu Liu, Esteban Mezey Background/Aim: The accumulation of reactive oxygen species (ROS) is important in the activation of hepatic stellate cells and fibrogenesis. This study determined the role of NADPH oxidase, which generates ROS, on fibrogenesis. METHODS: Human LX-2 stellate cells in culture and a CCL4 injury mouse model deficient in a key regulator of NADPH oxidase (gp91phox-/-) were used to study the role of NADPH oxidase in fibrogenesis. In the culture experiments, transient transfection of LX-2 stellate cells was performed using a luciferase construct containing the human α1(I) collagen promoter. Cells were then exposed to TGFβ (10ng/ml) with or without diphenyleneiodonium (DPI) a NADPH oxidase inhibitor. In the In Vivo experiments, wild-type (wt) or gp91phox-/- mice were subjected to CCl4 injections over 8 weeks (biweekly i.p. injection with 5ml/kg of 20% CCl4 solution in olive oil). RESULTS: In the transient transfections, DPI resulted in a marked decrease in the activity of α1(I) collagen gene expression both in the absence and presence of TGFβ. In the In Vivo experiments, serum AST and ALT levels were higher after CCL4 in the gp91phox-/- than in the wt animals, which correlated with increased necrosis on liver histology. However, a greater amount of stellate cell activation (αSMA immunostaining) and fibrosis (morphometric determination of sirius red stained slides) was seen in the CCL4 wt animals. By TUNEL assay, there was less apoptosis in the CCL4 gp91phox-/- mice. On western blot analysis, there was increased expression of matrix metalloproteinase 2 (MMP-2), tissue inhibitor metalloproteinase 1 (TIMP)-1 and TIMP-2 in the wt CCl4 but not the gp91phox-/- animals. CONCLUSION: Inhibition of NADPH oxidase suppresses the enhancement by TGFβ of the α1(I) collagen promoter. The gp91phox-/- CCl4 treated mice exhibited a greater amount of necrosis and less apoptosis in association with reduced fibrosis. The lack of increase after CCL4 in TIMP-1 and TIMP-2 protein in the gp91phox-/- as compared to the wild type mice is a likely factor for the decreased accumulation of fibrosis in the gp91phox-/- animals.
M1581 Anti-Copper Therapy Protects Against Hepatic Fibrosis By Down-Regulating Collagen Iα1 mRNA Expression in Hepatic Stellate Cells Ming Song, Zhenyuan Song, George Brewer, Craig J. McClain Background/Aims: Copper levels are elevated in a variety of clinical and experimental liver diseases, particularly in primary biliary cirrhosis, and anti-copper therapy is effective in protecting against murine models of hepatic fibrosis. The mechanism(s) of copper modulation of fibrogenesis remain elusive. Collagen type I is the main component of extracellular matrix produced by hepatic stellate cells. The aim of this study was to test if copper can modulate collagen I α 1 mRNA expression both In Vivo and In Vitro. Methods: Male C57BL/6J mice were divided into four groups: five for sham operation alone; five for sham operation plus tetrathiomolybdate (TM), a potent copper-chelating drug; ten for bile duct ligation (BDL) plus TM; and ten for BDL alone. In the TM-treated animals, TM was given at a daily dose of 0.9 mg by means of intragastric gavage, beginning 5 days before BDL. All the animals were killed 5 days after surgery. Liver tissues were harvested for histology study. LX2 cells (human hepatic stellate cell line) were treated with TM at various time and dose points. Total RNA and protein were isolated from liver tissues and cultured stellate cells, respectively. Collagen I α 1 mRNA expression was determined by real time RT-PCR. Western blot analysis was performed for protein expression. Results: Hepatic collagen deposition was significantly decreased and was paralleled by a significant suppression of hepatic smooth muscle α-actin (α-SMA) and collagen I α 1 mRNA expression in TM treated BDL mice. Incubation with TM significantly decreased collagen I α 1 mRNA expression in the time- and dose-dependent manner in LX2 cells. α-SMA expression was also inhibited by TM in a dose-dependent fashion in LX2 cells. Conclusions: Our results provide evidence that one mechanism involving anti-copper protection against hepatic fibrosis is through inhibition of hepatic stellate cell collagen I α 1 mRNA expression. These data provide further insights into understanding the role of copper and potential “anti-copper therapy” in liver fibrosis.
M1584 The Autonomic Neurotransmitter Acetylcholine Induces Fibrogenic Responses in Human Primary Hepatic Stellate Cells Morgan Maelle, Barbara Sigala, Clare Selden, Anna Mae Diehl, Jude A. Oben Background: Extra-neuronal acetylcholine (ACh) regulates organ repair. The role, however, of ACh in human hepatic fibrogenesis is unclear. We have previously shown that mouse hepatic stellate cells (HSC), the liver's principal fibrogenic cells, are regulated by ACh. The relevance of these animal studies to human fibrogenesis is unknown. There is evidence moreover, that vagal effects via ACh signalling modulate liver fat metabolism with pathogenic implications for non alcoholic fatty liver disease (NAFLD). Aim: To determine the effects of ACh on human primary HSC (hHSC) proliferation, collagen gene expression and release of pro-fibrogenic cytokines and to examine its involvement in NAFLD. Methods: Quiescent primary hHSC, isolated from healthy liver segments of patients (n≥3) undergoing resection of metastases, auto-fluoresced, with abundant glial fibrillary acidic protein (GFAP). Cultureinduced myofibroblastic transformation reduced GFAP and increased α-smooth muscle actin plus collagenI-α1 expression. Nicotinic, muscarinic acetylcholine receptors (nAChR, mAChR) and the ACh synthesising enzyme choline acetyl transferase (ChAT) presence was determined in hHSC and whole liver via semi-quantitative RT-PCR and immunocytochemistry. ACh(1nM-1mM) induced proliferation of myofibroblastic-hHSC in presence/absence of Mecamylamine(10uM, nAChR antagonist) and Atropine(10uM, mAChR antagonist) was assessed by a colorimetric assay. Induction of collagen1-α1 and transforming growth factor beta (TGF-β1) was assessed by QRT-PCR. Finally, RNA was extracted from livers of normal mice (n=3) fed a methionine and choline deficient diet (MCD), for 4 weeks, as a model of NASH, the more severe stage of NAFLD. Extracted RNA was assayed by Q-RT-PCR for differential upregulation of mAChR and nAChR. Results: hHSC express nAChR a1a, b1, 2, delta and epsilon receptors plus mAChR 1,2,3,4, 5 and ChAT. Whole liver expressed mAChR particularly m3, β1 and epsilon nAChR. ACh dose dependently induced hHSC proliferation with a near 200% increase at 1mM (p<0.05). This effect was significantly attenuated by atropine and mecamylamine. Collagen1-α1 and TGB-β1 were significantly induced by ACh (270-360%, p<0.05 and 150-180%, p<0.05 respectively). MCD fed mice had upregulated AChR gene expression compared with control. Conclusion: hHSC express functional AChR which are upregulated In Vivo. ACh induced proliferation of hHSC and increased collagen1α1 and TGF-β1 expression. Anti-cholinergic agents may have utility as anti-fibrotics in NASH.
M1582 Hedgehog Signaling Pathway in Primary Human Hepatic Stellate Cells Kevin D. Brown, Jude A Oben, Barbara Sigala, Liu Yang, Alessia Omenetti, Jason K. Sicklick, Hendrika Vandongen, Anna Mae Diehl Background/Aims: Hedgehog (Hh) signaling plays a key role in development and regulates proliferation, apoptosis, and differentiation of many cell types. We demonstrated increased expression of Hh pathway ligands and target genes in human hepatocellular carcinoma and primary biliary cirrhosis, as well as in rodent models of liver fibrosis and myofibroblastic cell lines derived from cirrhotic rat liver. These findings suggested to us that Hh signaling might modulate adult liver repair. However, this concept remains controversial because
AASLD Abstracts
A-798
little, if any, Hh pathway activity has ever been detected in healthy adult liver. Our Aim was to determine if primary human hepatic stellate cells (hHSC) produce and/or respond to Hh ligands. Selected findings were corroborated in the human LX2 cell line. Methods: Primary hHSCs were obtained from healthy liver segments of 2 patients undergoing resection of metastases. RNA was harvested from freshly isolated hHSC, and from hHSC cultured for 2, 4, and 10 days. Myofibroblastic activation was verified by Q-RT-PCR analysis of peroxisome proliferator activated receptor(PPAR)γ, transforming growth factor (TGF)β1, plasminogen activator inhibitor (PAI)-1, α-smooth muscle actin (αSMA) and collagenIα1. Expression of Hh pathway ligands (sonic and indian hedgehog , shh and ihh), receptor (patched), coreceptor (smoothened), Hh-regulated target genes (gli1, gli2, gli3), as well the Hh inhibitor, Hedgehog interacting peptide (hip), were correlated with activation. Expression of these mRNAs was also assessed in LX2 cells. To investigate the effect of Hh signaling, caspase 3/ 7 activity was compared in LX2 cells treated with Hh-neutralizing antibodies or control IgG. Results: Primary hHSC expression of PPARγ fell by 80%, while TGFβ1, PAI-1, αSMA, and collagen respectively increased 4-, 2-, 140- and 400- fold during 10-day culture. During this time, expression of both Hh ligands doubled, Hip expression fell, and expression of 2 Hh target genes, Gli2 and Gli3, increased at least 2 fold. Cultured LX2 cells also expressed mRNAs for Hh pathway ligands, signaling components, and target genes. Treatment of LX2 cells with Hh-neutralizing antibodies increased caspase 3/7 activity (p < 0.05). Conclusion: Primary HSC from healthy human livers express Hh ligands, signaling components and target genes, and expression of these mRNAs increases as HSC become myofibroblastic. Moreover, inhibiting Hh signaling in myofibroblastic human HSC increases apoptosis. These findings suggest that Hh signaling occurs during remodeling of human adult livers.
M1580
AASLD Abstracts
Loss of Hepatic Stellate Cell Lipid Droplets Does Not Contribute to Stellate Cell Activation and Liver Fibrosis Johannes Kluwe, Nuttaporn Wongsiriroj, Roseann Zott, William S. Blaner, Robert F. Schwabe Background: Following liver injury, hepatic stellate cells (HSCs) undergo a well described activation process that transforms them from a vitamin A-storing to a myofibroblast-like cell type. One of the most striking features of this transformation is the gradual loss of vitamin A-containing lipid droplets which is not only considered a hallmark of activation but also an essential event that drives the HSC activation process. However, the exact contribution of lipid droplets to HSC activation and fibrogenesis remains largely unknown. Aim: To determine whether the absence of HSC lipid droplets promotes fibrogenesis in a genetic mouse model that lacks lipid droplets in HSCs. Methods: The role of lipid droplets in HSC activation and fibrogenesis was investigated in lecithin:retinol acyltransferase (LRAT)deficient mice which display an absence of hepatic retinyl esters and a complete lack of lipid droplets in HSCs. Experimental fibrogenesis was induced by ligation of the common bile duct (BDL) or by injection of either 1 or 8 doses of CCl4 (0.5 µl/g body weight). Spontaneous and experimental fibrosis was evaluated by Sirius red staining, αSMA protein content and mRNA levels of collagen α1(I), TIMP-1 and αSMA as determined by quantitative real time PCR. Results: LRAT-deficient mice did not display an increase in spontaneous fibrosis at the age of three months as determined by Sirius red staining and mRNA levels of collagen α1(I), TIMP-1 and αSMA. Interestingly, there was also no difference in the degree of liver fibrosis between wild-type and LRAT-deficient mice after 1 or 8 injections of CCl4 as judged by Sirius Red staining, αSMA western blot and mRNA levels for collagen α1(I) and TIMP-1. This data was further confirmed using BDL as a second model of experimental fibrogenesis. After 3 weeks of BDL, wild-type and LRAT-deficient mice displayed the same degree of liver fibrosis. Conclusion: The absence of increased spontaneous and experimental fibrosis in LRAT-deficient mice suggests that the loss of lipid droplets does not drive HSC activation and liver fibrosis. Thus, lipid/vitamin A storage and extracellular matrix synthesis are two important, yet unrelated functions of HSCs.
M1583 Inhibition of NADPH Oxidase Suppresses Fibrogenesis Ghazaleh Aram, James J. Potter, Xiaopu Liu, Esteban Mezey Background/Aim: The accumulation of reactive oxygen species (ROS) is important in the activation of hepatic stellate cells and fibrogenesis. This study determined the role of NADPH oxidase, which generates ROS, on fibrogenesis. METHODS: Human LX-2 stellate cells in culture and a CCL4 injury mouse model deficient in a key regulator of NADPH oxidase (gp91phox-/-) were used to study the role of NADPH oxidase in fibrogenesis. In the culture experiments, transient transfection of LX-2 stellate cells was performed using a luciferase construct containing the human α1(I) collagen promoter. Cells were then exposed to TGFβ (10ng/ml) with or without diphenyleneiodonium (DPI) a NADPH oxidase inhibitor. In the In Vivo experiments, wild-type (wt) or gp91phox-/- mice were subjected to CCl4 injections over 8 weeks (biweekly i.p. injection with 5ml/kg of 20% CCl4 solution in olive oil). RESULTS: In the transient transfections, DPI resulted in a marked decrease in the activity of α1(I) collagen gene expression both in the absence and presence of TGFβ. In the In Vivo experiments, serum AST and ALT levels were higher after CCL4 in the gp91phox-/- than in the wt animals, which correlated with increased necrosis on liver histology. However, a greater amount of stellate cell activation (αSMA immunostaining) and fibrosis (morphometric determination of sirius red stained slides) was seen in the CCL4 wt animals. By TUNEL assay, there was less apoptosis in the CCL4 gp91phox-/- mice. On western blot analysis, there was increased expression of matrix metalloproteinase 2 (MMP-2), tissue inhibitor metalloproteinase 1 (TIMP)-1 and TIMP-2 in the wt CCl4 but not the gp91phox-/- animals. CONCLUSION: Inhibition of NADPH oxidase suppresses the enhancement by TGFβ of the α1(I) collagen promoter. The gp91phox-/- CCl4 treated mice exhibited a greater amount of necrosis and less apoptosis in association with reduced fibrosis. The lack of increase after CCL4 in TIMP-1 and TIMP-2 protein in the gp91phox-/- as compared to the wild type mice is a likely factor for the decreased accumulation of fibrosis in the gp91phox-/- animals.
M1581 Anti-Copper Therapy Protects Against Hepatic Fibrosis By Down-Regulating Collagen Iα1 mRNA Expression in Hepatic Stellate Cells Ming Song, Zhenyuan Song, George Brewer, Craig J. McClain Background/Aims: Copper levels are elevated in a variety of clinical and experimental liver diseases, particularly in primary biliary cirrhosis, and anti-copper therapy is effective in protecting against murine models of hepatic fibrosis. The mechanism(s) of copper modulation of fibrogenesis remain elusive. Collagen type I is the main component of extracellular matrix produced by hepatic stellate cells. The aim of this study was to test if copper can modulate collagen I α 1 mRNA expression both In Vivo and In Vitro. Methods: Male C57BL/6J mice were divided into four groups: five for sham operation alone; five for sham operation plus tetrathiomolybdate (TM), a potent copper-chelating drug; ten for bile duct ligation (BDL) plus TM; and ten for BDL alone. In the TM-treated animals, TM was given at a daily dose of 0.9 mg by means of intragastric gavage, beginning 5 days before BDL. All the animals were killed 5 days after surgery. Liver tissues were harvested for histology study. LX2 cells (human hepatic stellate cell line) were treated with TM at various time and dose points. Total RNA and protein were isolated from liver tissues and cultured stellate cells, respectively. Collagen I α 1 mRNA expression was determined by real time RT-PCR. Western blot analysis was performed for protein expression. Results: Hepatic collagen deposition was significantly decreased and was paralleled by a significant suppression of hepatic smooth muscle α-actin (α-SMA) and collagen I α 1 mRNA expression in TM treated BDL mice. Incubation with TM significantly decreased collagen I α 1 mRNA expression in the time- and dose-dependent manner in LX2 cells. α-SMA expression was also inhibited by TM in a dose-dependent fashion in LX2 cells. Conclusions: Our results provide evidence that one mechanism involving anti-copper protection against hepatic fibrosis is through inhibition of hepatic stellate cell collagen I α 1 mRNA expression. These data provide further insights into understanding the role of copper and potential “anti-copper therapy” in liver fibrosis.
M1584 The Autonomic Neurotransmitter Acetylcholine Induces Fibrogenic Responses in Human Primary Hepatic Stellate Cells Morgan Maelle, Barbara Sigala, Clare Selden, Anna Mae Diehl, Jude A. Oben Background: Extra-neuronal acetylcholine (ACh) regulates organ repair. The role, however, of ACh in human hepatic fibrogenesis is unclear. We have previously shown that mouse hepatic stellate cells (HSC), the liver's principal fibrogenic cells, are regulated by ACh. The relevance of these animal studies to human fibrogenesis is unknown. There is evidence moreover, that vagal effects via ACh signalling modulate liver fat metabolism with pathogenic implications for non alcoholic fatty liver disease (NAFLD). Aim: To determine the effects of ACh on human primary HSC (hHSC) proliferation, collagen gene expression and release of pro-fibrogenic cytokines and to examine its involvement in NAFLD. Methods: Quiescent primary hHSC, isolated from healthy liver segments of patients (n≥3) undergoing resection of metastases, auto-fluoresced, with abundant glial fibrillary acidic protein (GFAP). Cultureinduced myofibroblastic transformation reduced GFAP and increased α-smooth muscle actin plus collagenI-α1 expression. Nicotinic, muscarinic acetylcholine receptors (nAChR, mAChR) and the ACh synthesising enzyme choline acetyl transferase (ChAT) presence was determined in hHSC and whole liver via semi-quantitative RT-PCR and immunocytochemistry. ACh(1nM-1mM) induced proliferation of myofibroblastic-hHSC in presence/absence of Mecamylamine(10uM, nAChR antagonist) and Atropine(10uM, mAChR antagonist) was assessed by a colorimetric assay. Induction of collagen1-α1 and transforming growth factor beta (TGF-β1) was assessed by QRT-PCR. Finally, RNA was extracted from livers of normal mice (n=3) fed a methionine and choline deficient diet (MCD), for 4 weeks, as a model of NASH, the more severe stage of NAFLD. Extracted RNA was assayed by Q-RT-PCR for differential upregulation of mAChR and nAChR. Results: hHSC express nAChR a1a, b1, 2, delta and epsilon receptors plus mAChR 1,2,3,4, 5 and ChAT. Whole liver expressed mAChR particularly m3, β1 and epsilon nAChR. ACh dose dependently induced hHSC proliferation with a near 200% increase at 1mM (p<0.05). This effect was significantly attenuated by atropine and mecamylamine. Collagen1-α1 and TGB-β1 were significantly induced by ACh (270-360%, p<0.05 and 150-180%, p<0.05 respectively). MCD fed mice had upregulated AChR gene expression compared with control. Conclusion: hHSC express functional AChR which are upregulated In Vivo. ACh induced proliferation of hHSC and increased collagen1α1 and TGF-β1 expression. Anti-cholinergic agents may have utility as anti-fibrotics in NASH.
M1582 Hedgehog Signaling Pathway in Primary Human Hepatic Stellate Cells Kevin D. Brown, Jude A Oben, Barbara Sigala, Liu Yang, Alessia Omenetti, Jason K. Sicklick, Hendrika Vandongen, Anna Mae Diehl Background/Aims: Hedgehog (Hh) signaling plays a key role in development and regulates proliferation, apoptosis, and differentiation of many cell types. We demonstrated increased expression of Hh pathway ligands and target genes in human hepatocellular carcinoma and primary biliary cirrhosis, as well as in rodent models of liver fibrosis and myofibroblastic cell lines derived from cirrhotic rat liver. These findings suggested to us that Hh signaling might modulate adult liver repair. However, this concept remains controversial because
AASLD Abstracts
A-798