- Email: [email protected]
162 Progressive Matrix Crosslinking Limits Reversibility of Liver Fibrosis and is Independent of Tissue Transglutaminase
162
adiponectin overexpressing animals compared to controls. Stellate cells isolated from WT FVB animals were exposed to a lentivirus encoding adiponectin; expression of the “adipogenic” transcriptional program including PPARgamma, SREBP1c and CEBP alpha mRNA were significantly elevated by 3.2, 4.1, 2.2 fold, respectively (n=3, p < 0.05 for adiponectin virus vs. control virus, @ 100 MOI). Troglitazone strongly suppressed the up-regulation of collagen1A1 and SM alpha actin in stellate cells isolated from WT mice. However stellate cells from ADN null animals failed to respond to troglitazone. Further, in isolated stellate cells (again from FVB mice), in which lentivirus was used to over express adiponectin, while at the same time knocking out PPARgamma with an adenovirus-Cre-recombinase system, revealed that adiponectin significantly inhibited collagen1A1 and SMA actin. Conclusions. We have demonstrated that the PPARgamma effect on the fibrogenic cascade in hepatic stellate cells is dependent on adiponectin. Further, the data suggest that there are both PPARgamma dependent and independent pathways involved in PPARgamma's effect on fibrogenesis. Understanding the signaling events important in PPARgamma and adiponectin mediated effects on stellate cells may help in developing new therapies for liver fibrosis.
Progressive Matrix Crosslinking Limits Reversibility of Liver Fibrosis and is Independent of Tissue Transglutaminase Yury Popov, Deanna Sverdlov, Anisha Sharma, Detlef Schuppan Background: Targeting extracellular matrix stability is an attractive antifibrotic strategy. Prior studies have suggested a role for tissue transglutaminase-mediated collagen crosslinking in matrix stabilization, but the extent and mechanisms remain poorly understood. We therefore used a quantitative biochemical approach to characterize dynamic changes in collagen crosslinking during progression and reversal of CCL4-induced liver fibrosis in wildtype mice and in mice deficient in transglutaminase 2 (TG2), the predominant transglutaminase isoform in the liver. Materials and Methods: Liver fibrosis was induced in TG2-/- mice and wildtype littermates (C57BL6) by repeated gavage with carbon tetrachloride (CCL4) 3x per week for 1, 3, 6 and 12 weeks. Fibrosis reversal was monitored for up to 36 weeks after CCL4 withdrawal. Collagen crosslinking was measured by sequential extraction using neutral salt, acetic acid and pepsin. Collagen was quantified biochemically via hydroxyproline in the livers, in the extracts and in residual liver tissue. This was correlated to histological evolution and transcript levels of fibrosis related genes. Results: In normal liver, neutral salt, acetic acid and pepsin solubilized 3.2, 1.2% and 91% of total collagen, respectively, while 4.5% remained insoluble, representing a highly cross-linked collagenous matrix. CCL4 administration for 12w led to development of cirrhosis and a 6-fold increase in total liver collagen. Collagen solubility during fibrosis progression revealed progressive cross-linking, with an increase of the insoluble collagen fraction to 27% (6-fold) at week 12 at the expense of the pepsin-soluble fraction. The salt- and acid-soluble collagen fractions, representing freshly synthesized collagen, remained constant at 5% of total collagen. The extent of matrix deposition and stabilization remained constant up to 36 weeks after discontinuation of CCL4. Furthermore, no difference in collagen solubility and no fibrosis reversal or change in matrix-related transcripts were found in TG2-/- vs. wildtype mice during all time points of progression or follow-up. Conclusions: 1) Quantitative measurement of fibrotic matrix stability revealed a significant increase of collagen crosslinking, which parallels fibrosis progression and limits its reversal. 2) Matrix stabilization in fibrotic liver is independent of transglutaminase-mediated cross-linking since it was unaffected in TG2-/- mice 3) This TG2independent collagen cross-linking is an important target for future antifibrotic therapies.
165
BACKGROUND and AIMS: T-cell derived microparticles (MP) can induce a fibrolytic phenotype in myofibroblastic hepatic stellate cells (HSC; Kornek M et al, EASL 2009). However, the molecules that are involved in the observed mechanism of fibrolysis induction remained unknown. METHODS: The Jurkat T cell line and human peripheral CD4 and CD8 T cells were used naïve or after activation with phytohaemagglutinin (PHA). T-cell apoptosis was induced by Staurosporine. MP were obtained from the T cell supernatants as the fraction sedimenting between 10,000 and 100,000g and quantified by FACS analysis for the T cell marker CD3 and MP marker Annexin V. Membrane molecules which could be implicated in the induction of fibrolysis were identified by MALDI-TOF mass spectrometry of MP as compared to hepatocyte MP, and their surface expression was validated by FACS analysis. Selected membrane molecules were neutralized with blocking or IgG matched control antibodies on MP prior to their incubation with HSC or HSC (LX-2, kind gift of Dr. S.L. Friedman, NY) were pre-incubated with ICAM-1 blocking antibody. Profibrogenic and putative fibrolytic transcripts were quantified by realtime quantitative PCR. Apoptosis was assessed by Annexin V and 7AAD (7-amino-actinomycin D) FACS analysis. RESULTS: Among several cell-cell adhesion molecules only blocking of ICAM-1 (CD54) significantly reduced (40%, p<0.05) MP fusion with HSC membranes. MALDI-TOF mass spectrometry of the MP revealed candidate trans-membrane molecules, especially CD147/Emmprin, which could be implicated to induce fibrolytic activation of HSC. FACS analysis showed that MP were highly positive for CD147. Blocking of CD147 on MP resulted in a significant reduction of MMPinduction in HSC (MMP-3: 38%, MMP-13: 23%, p<0.05) compared to addition of MP incubated with control IgG. T-cell derived MP did not induce apoptosis or necrosis in HSC after 24hrs of incubation. MP fusion led to nuclear NFkB translocation in HSC and MMPinduction was significantly diminished after NFkB signal pathway blocking. CONCLUSIONS: 1. Fusion of T cell derived MP with HSC membranes is (partly) dependent on ICAM-1 (CD54) expressed on HSC. 2. Induction of fibrolysis in HSC is partly mediated by (transfer of) CD147 expressed on MP. 3. MP-induced MMP expression in HSC was NFkB dependent. 4. These effects were not related to MP-induced HSC apoptosis.
163 KLF11 Displays Antifibrogenic Effects by Transcriptional Silencing of Most of the Collagen Genes in Hepatic Stellate Cells Charanjit S. Virk, Angela J. Mathison, Cathrine J. DeMars, Uday Shergill, Ann Liebl, Gwen A. Lomberk, Usman Yaqoob, Soujanya Sodavarapu, Martin E. Fernandez-Zapico, Vijay Shah, Navtej Buttar, Raul A. Urrutia Stellate cells play a crucial role in tissue remodeling during liver injury. The molecular pathways critical for the function of these cells remain to be further characterized. KLF11, a member of the Kruppel-like factor (KLF) family that regulates embryonal differentiation, is emerging as an important transcriptional regulator during injury and repair. The aim of this study was to examine the role of KLF11 in stellate cell function and their response to injury. Well characterized human LX2 stellate cells were infected with control or KLF11 expressing adenovirus to examine the expression of proteins involved in stromal remodeling. For the In-Vivo effect of injury on stellate cell activation, KLF11-/- and wild type mice were treated with phenobarbital in water followed by twice weekly injections of 0.5mg/kg of CCL4 IP in olive oil. Six weeks later, animals were sacrificed and liver tissue was snap frozen. Array analysis using pathway reconstruction algorithms show that KLF11 downregulates (> 1.5 fold) mRNA levels of several collagens including Ia, Ia2, III, Va1, XIa1. Congruent, with these in-vitro findings, CCL4 injury in KLF11 -/- mice resulted in increased stellate cell activation and fibrosis compared to KLF11 +/+ mice as assessed by histochemical staining for PDGFR, Collagen Ia2, aSMA, desmin and vimentin (PDGFR staiing, Left panel KLF11-/, right panel KLF11+/+). To gain further insight into the mechanisms by which KLF11 modulate the collagen gene transcription, we used the collagen Ia2 promoter as a model. Indeed, KLF11 binds to and repress this promoter (90.2+ 1.4% repression P<0.05). Site directed mutagenesis of KLF11 suggests that posttranslational modification by signaling pathways including EGFR-GSK-AKT could modulate this repression indicating that this antifibrogenic effects can be further modulated by signaling. Collectively, these results demonstrate that besides KLF6, KLF11 is another member of Kruppel family which is critical for Stellate Cell Biology. The antifibrogenic effects of KLF11 reported here expand significantly our understanding of molecular mechanism underlying the regulation of liver fibrosis
232 The Underdiagnosis of Pediatric Hepatitis C: An Emerging Health Care Issue in Florida Aymin Delgado-Borrego, Lesley J. Smith, Maureen M. Jonas, Cyndena A. Hall, Betania Negre, Tracie L. Miller, Regino P. Gonzalez-Peralta, Raymond T. Chung Background: Hepatitis C virus (HCV) infection is the most common chronic liver disease and the leading indication for liver transplantation among adults in the U.S. Based on the 3rd National Health and Nutrition Examination Survey (NHANES), approximately 0.2 to 0.4% of the pediatric population (6 to 19 years-old) are anti-HCV Ab(+), approximately 75% of whom are chronically infected. Hepatitis C is a reportable disease in Florida (FL). Aims: To assess the adequacy of reporting of pediatric HCV in FL. Methods: We included children (<19 yrs-old) in the Merlin database, which registers all reported cases of HCV infection in FL from 2000-2008. We classified HCV infection as confirmed [HCV RNA(+) or anti-HCV (+) signal-to-cut off>3.8], probable [anti-HCV(+) and ALT level>upper limit of normal, HCV RNA unverified], or suspect [anti-HCV(+)]. We compared the number of actual cases of pediatric HCV in FL from the Merlin database to the number expected based on NHANES (average 0.3%) and U.S. Census Bureau data. We analyzed pediatric HCV by age group, race/ethnicity, and geographic distribution by FL County. Results: We identified 1,755 unique cases of pediatric HCV in FL (1,167 from 2000-2006, 318 cases in 2007, and 270 in 2008). This represents only 14.4% of the expected prevalent cases in 2008 (12,155). This is in contrast to 46.3% of adult (>=19yo) cases of HCV identified in FL. Among children with HCV infection in FL, 37.1% were confirmed, 1.9% were probable, and 61% were suspect cases. Of these 844 (48.1%) were females, 621 (35.4%) Caucasian, 168 (9.6%) African American, 5 (0.3%) Asian and 961 (54.7%) “other” or unknown. Fifty one percent were between 0-12 years old, and 49% were between 13-18 years, with 40% between 16-18 years. Dade [402 (22.9%)] and Broward [197 (11.2%)] counties contributed the largest percentages of identified cases. We estimated that no more than 150 (8.5%) of the 1755 identified cases have been evaluated by a pediatric hepatologist. Conclusion: Only a minority of expected pediatric HCV cases are identified in FL, which constitutes a critical public health problem. Although under-reporting of this infection is possible, the number of identified children with HCV who are receiving appropriate medical care is unacceptably low. Implication: Appropriate strategies to increase awareness of this condition and test individuals at risk through modification of public health policy can be expected to improve morbidity, mortality, and reduce health care costs.
164 Elucidating Adiponectin's Role in Liver Fibrosis-Analysis of Stellate Cell Biology in Adiponectin Transgenic Mice Mahnoush S. Shafiei, Don C. Rockey Background. The adipose tissue secreted cytokine, adiponectin, has been suggested to play an important role in the pathogenesis of liver fibrosis. Adiponectin is expressed in stellate cells in the liver, and appears to inhibit their fibrogenic phenotype. This study was designed to help further elucidate the mechanism by which adiponectin modulates hepatic stellate cell fibrogenesis. Methods. Homozygous adiponectin null and heterozygous adiponectin overexpressing mice and the corresponding controls on the FVB background were used. To induce liver fibrosis, the mice were given intraperitoneal injections of 0.2g/kg body weight of thioacetamide (TAA). Stellate cells were isolated, grown for two days and then manipulated. In order to determine whether PPARgamma ligands can prevent HSC activation in the absence of adiponectin, stellate cells from KO and WT mice were exposed to the PPARgamma agonist, troglitazone. To understand if adiponectin could promote HSC quiescence, independent of PPARgamma, PPARgamma was depleted in by using an adenovirus-Cre -recombinase system. Results. We found that adiponectin overexpressing mice receiving TAA were resistant to fibrosis compared to controls. In contrast, adiponectin KO animals developed severe fibrosis. Expression of collagen1A1 and SM alpha actin were significantly lower in
S-779
AASLD Abstracts
AASLD Abstracts
T-Cell Derived Microparticles Induce Fibrolytic Activation of Hepatic Stellate Cells via ICAM-1 (CD54) Dependent Uptake and Emmprin (CD147) Miroslaw Kornek, Yury Popov, Towia Libermann, Detlef Schuppan
adiponectin overexpressing animals compared to controls. Stellate cells isolated from WT FVB animals were exposed to a lentivirus encoding adiponectin; expression of the “adipogenic” transcriptional program including PPARgamma, SREBP1c and CEBP alpha mRNA were significantly elevated by 3.2, 4.1, 2.2 fold, respectively (n=3, p < 0.05 for adiponectin virus vs. control virus, @ 100 MOI). Troglitazone strongly suppressed the up-regulation of collagen1A1 and SM alpha actin in stellate cells isolated from WT mice. However stellate cells from ADN null animals failed to respond to troglitazone. Further, in isolated stellate cells (again from FVB mice), in which lentivirus was used to over express adiponectin, while at the same time knocking out PPARgamma with an adenovirus-Cre-recombinase system, revealed that adiponectin significantly inhibited collagen1A1 and SMA actin. Conclusions. We have demonstrated that the PPARgamma effect on the fibrogenic cascade in hepatic stellate cells is dependent on adiponectin. Further, the data suggest that there are both PPARgamma dependent and independent pathways involved in PPARgamma's effect on fibrogenesis. Understanding the signaling events important in PPARgamma and adiponectin mediated effects on stellate cells may help in developing new therapies for liver fibrosis.
Progressive Matrix Crosslinking Limits Reversibility of Liver Fibrosis and is Independent of Tissue Transglutaminase Yury Popov, Deanna Sverdlov, Anisha Sharma, Detlef Schuppan Background: Targeting extracellular matrix stability is an attractive antifibrotic strategy. Prior studies have suggested a role for tissue transglutaminase-mediated collagen crosslinking in matrix stabilization, but the extent and mechanisms remain poorly understood. We therefore used a quantitative biochemical approach to characterize dynamic changes in collagen crosslinking during progression and reversal of CCL4-induced liver fibrosis in wildtype mice and in mice deficient in transglutaminase 2 (TG2), the predominant transglutaminase isoform in the liver. Materials and Methods: Liver fibrosis was induced in TG2-/- mice and wildtype littermates (C57BL6) by repeated gavage with carbon tetrachloride (CCL4) 3x per week for 1, 3, 6 and 12 weeks. Fibrosis reversal was monitored for up to 36 weeks after CCL4 withdrawal. Collagen crosslinking was measured by sequential extraction using neutral salt, acetic acid and pepsin. Collagen was quantified biochemically via hydroxyproline in the livers, in the extracts and in residual liver tissue. This was correlated to histological evolution and transcript levels of fibrosis related genes. Results: In normal liver, neutral salt, acetic acid and pepsin solubilized 3.2, 1.2% and 91% of total collagen, respectively, while 4.5% remained insoluble, representing a highly cross-linked collagenous matrix. CCL4 administration for 12w led to development of cirrhosis and a 6-fold increase in total liver collagen. Collagen solubility during fibrosis progression revealed progressive cross-linking, with an increase of the insoluble collagen fraction to 27% (6-fold) at week 12 at the expense of the pepsin-soluble fraction. The salt- and acid-soluble collagen fractions, representing freshly synthesized collagen, remained constant at 5% of total collagen. The extent of matrix deposition and stabilization remained constant up to 36 weeks after discontinuation of CCL4. Furthermore, no difference in collagen solubility and no fibrosis reversal or change in matrix-related transcripts were found in TG2-/- vs. wildtype mice during all time points of progression or follow-up. Conclusions: 1) Quantitative measurement of fibrotic matrix stability revealed a significant increase of collagen crosslinking, which parallels fibrosis progression and limits its reversal. 2) Matrix stabilization in fibrotic liver is independent of transglutaminase-mediated cross-linking since it was unaffected in TG2-/- mice 3) This TG2independent collagen cross-linking is an important target for future antifibrotic therapies.
165
BACKGROUND and AIMS: T-cell derived microparticles (MP) can induce a fibrolytic phenotype in myofibroblastic hepatic stellate cells (HSC; Kornek M et al, EASL 2009). However, the molecules that are involved in the observed mechanism of fibrolysis induction remained unknown. METHODS: The Jurkat T cell line and human peripheral CD4 and CD8 T cells were used naïve or after activation with phytohaemagglutinin (PHA). T-cell apoptosis was induced by Staurosporine. MP were obtained from the T cell supernatants as the fraction sedimenting between 10,000 and 100,000g and quantified by FACS analysis for the T cell marker CD3 and MP marker Annexin V. Membrane molecules which could be implicated in the induction of fibrolysis were identified by MALDI-TOF mass spectrometry of MP as compared to hepatocyte MP, and their surface expression was validated by FACS analysis. Selected membrane molecules were neutralized with blocking or IgG matched control antibodies on MP prior to their incubation with HSC or HSC (LX-2, kind gift of Dr. S.L. Friedman, NY) were pre-incubated with ICAM-1 blocking antibody. Profibrogenic and putative fibrolytic transcripts were quantified by realtime quantitative PCR. Apoptosis was assessed by Annexin V and 7AAD (7-amino-actinomycin D) FACS analysis. RESULTS: Among several cell-cell adhesion molecules only blocking of ICAM-1 (CD54) significantly reduced (40%, p<0.05) MP fusion with HSC membranes. MALDI-TOF mass spectrometry of the MP revealed candidate trans-membrane molecules, especially CD147/Emmprin, which could be implicated to induce fibrolytic activation of HSC. FACS analysis showed that MP were highly positive for CD147. Blocking of CD147 on MP resulted in a significant reduction of MMPinduction in HSC (MMP-3: 38%, MMP-13: 23%, p<0.05) compared to addition of MP incubated with control IgG. T-cell derived MP did not induce apoptosis or necrosis in HSC after 24hrs of incubation. MP fusion led to nuclear NFkB translocation in HSC and MMPinduction was significantly diminished after NFkB signal pathway blocking. CONCLUSIONS: 1. Fusion of T cell derived MP with HSC membranes is (partly) dependent on ICAM-1 (CD54) expressed on HSC. 2. Induction of fibrolysis in HSC is partly mediated by (transfer of) CD147 expressed on MP. 3. MP-induced MMP expression in HSC was NFkB dependent. 4. These effects were not related to MP-induced HSC apoptosis.
163 KLF11 Displays Antifibrogenic Effects by Transcriptional Silencing of Most of the Collagen Genes in Hepatic Stellate Cells Charanjit S. Virk, Angela J. Mathison, Cathrine J. DeMars, Uday Shergill, Ann Liebl, Gwen A. Lomberk, Usman Yaqoob, Soujanya Sodavarapu, Martin E. Fernandez-Zapico, Vijay Shah, Navtej Buttar, Raul A. Urrutia Stellate cells play a crucial role in tissue remodeling during liver injury. The molecular pathways critical for the function of these cells remain to be further characterized. KLF11, a member of the Kruppel-like factor (KLF) family that regulates embryonal differentiation, is emerging as an important transcriptional regulator during injury and repair. The aim of this study was to examine the role of KLF11 in stellate cell function and their response to injury. Well characterized human LX2 stellate cells were infected with control or KLF11 expressing adenovirus to examine the expression of proteins involved in stromal remodeling. For the In-Vivo effect of injury on stellate cell activation, KLF11-/- and wild type mice were treated with phenobarbital in water followed by twice weekly injections of 0.5mg/kg of CCL4 IP in olive oil. Six weeks later, animals were sacrificed and liver tissue was snap frozen. Array analysis using pathway reconstruction algorithms show that KLF11 downregulates (> 1.5 fold) mRNA levels of several collagens including Ia, Ia2, III, Va1, XIa1. Congruent, with these in-vitro findings, CCL4 injury in KLF11 -/- mice resulted in increased stellate cell activation and fibrosis compared to KLF11 +/+ mice as assessed by histochemical staining for PDGFR, Collagen Ia2, aSMA, desmin and vimentin (PDGFR staiing, Left panel KLF11-/, right panel KLF11+/+). To gain further insight into the mechanisms by which KLF11 modulate the collagen gene transcription, we used the collagen Ia2 promoter as a model. Indeed, KLF11 binds to and repress this promoter (90.2+ 1.4% repression P<0.05). Site directed mutagenesis of KLF11 suggests that posttranslational modification by signaling pathways including EGFR-GSK-AKT could modulate this repression indicating that this antifibrogenic effects can be further modulated by signaling. Collectively, these results demonstrate that besides KLF6, KLF11 is another member of Kruppel family which is critical for Stellate Cell Biology. The antifibrogenic effects of KLF11 reported here expand significantly our understanding of molecular mechanism underlying the regulation of liver fibrosis
232 The Underdiagnosis of Pediatric Hepatitis C: An Emerging Health Care Issue in Florida Aymin Delgado-Borrego, Lesley J. Smith, Maureen M. Jonas, Cyndena A. Hall, Betania Negre, Tracie L. Miller, Regino P. Gonzalez-Peralta, Raymond T. Chung Background: Hepatitis C virus (HCV) infection is the most common chronic liver disease and the leading indication for liver transplantation among adults in the U.S. Based on the 3rd National Health and Nutrition Examination Survey (NHANES), approximately 0.2 to 0.4% of the pediatric population (6 to 19 years-old) are anti-HCV Ab(+), approximately 75% of whom are chronically infected. Hepatitis C is a reportable disease in Florida (FL). Aims: To assess the adequacy of reporting of pediatric HCV in FL. Methods: We included children (<19 yrs-old) in the Merlin database, which registers all reported cases of HCV infection in FL from 2000-2008. We classified HCV infection as confirmed [HCV RNA(+) or anti-HCV (+) signal-to-cut off>3.8], probable [anti-HCV(+) and ALT level>upper limit of normal, HCV RNA unverified], or suspect [anti-HCV(+)]. We compared the number of actual cases of pediatric HCV in FL from the Merlin database to the number expected based on NHANES (average 0.3%) and U.S. Census Bureau data. We analyzed pediatric HCV by age group, race/ethnicity, and geographic distribution by FL County. Results: We identified 1,755 unique cases of pediatric HCV in FL (1,167 from 2000-2006, 318 cases in 2007, and 270 in 2008). This represents only 14.4% of the expected prevalent cases in 2008 (12,155). This is in contrast to 46.3% of adult (>=19yo) cases of HCV identified in FL. Among children with HCV infection in FL, 37.1% were confirmed, 1.9% were probable, and 61% were suspect cases. Of these 844 (48.1%) were females, 621 (35.4%) Caucasian, 168 (9.6%) African American, 5 (0.3%) Asian and 961 (54.7%) “other” or unknown. Fifty one percent were between 0-12 years old, and 49% were between 13-18 years, with 40% between 16-18 years. Dade [402 (22.9%)] and Broward [197 (11.2%)] counties contributed the largest percentages of identified cases. We estimated that no more than 150 (8.5%) of the 1755 identified cases have been evaluated by a pediatric hepatologist. Conclusion: Only a minority of expected pediatric HCV cases are identified in FL, which constitutes a critical public health problem. Although under-reporting of this infection is possible, the number of identified children with HCV who are receiving appropriate medical care is unacceptably low. Implication: Appropriate strategies to increase awareness of this condition and test individuals at risk through modification of public health policy can be expected to improve morbidity, mortality, and reduce health care costs.
164 Elucidating Adiponectin's Role in Liver Fibrosis-Analysis of Stellate Cell Biology in Adiponectin Transgenic Mice Mahnoush S. Shafiei, Don C. Rockey Background. The adipose tissue secreted cytokine, adiponectin, has been suggested to play an important role in the pathogenesis of liver fibrosis. Adiponectin is expressed in stellate cells in the liver, and appears to inhibit their fibrogenic phenotype. This study was designed to help further elucidate the mechanism by which adiponectin modulates hepatic stellate cell fibrogenesis. Methods. Homozygous adiponectin null and heterozygous adiponectin overexpressing mice and the corresponding controls on the FVB background were used. To induce liver fibrosis, the mice were given intraperitoneal injections of 0.2g/kg body weight of thioacetamide (TAA). Stellate cells were isolated, grown for two days and then manipulated. In order to determine whether PPARgamma ligands can prevent HSC activation in the absence of adiponectin, stellate cells from KO and WT mice were exposed to the PPARgamma agonist, troglitazone. To understand if adiponectin could promote HSC quiescence, independent of PPARgamma, PPARgamma was depleted in by using an adenovirus-Cre -recombinase system. Results. We found that adiponectin overexpressing mice receiving TAA were resistant to fibrosis compared to controls. In contrast, adiponectin KO animals developed severe fibrosis. Expression of collagen1A1 and SM alpha actin were significantly lower in
S-779
AASLD Abstracts
AASLD Abstracts
T-Cell Derived Microparticles Induce Fibrolytic Activation of Hepatic Stellate Cells via ICAM-1 (CD54) Dependent Uptake and Emmprin (CD147) Miroslaw Kornek, Yury Popov, Towia Libermann, Detlef Schuppan