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Abstract

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References

This report is a summary of Ron Thurman Symposium on the Mechanisms of Alcohol-Induced Hepatic Fibrosis which was organized by The National Institutes of Health in Santa Barbara, California, June 25, 2005. The Symposium and this report highlight the unique aspects by which drinking alcoholic beverages may result in hepatic fibrosis. Acetaldehyde, the first metabolite of ethanol, can upregulate transcription of collagen I directly as well as indirectly by upregulating the synthesis of transforming growth factor-beta 1 (TGF-β1). Reactive oxygen species (ROS) generated in hepatocytes by alcohol metabolism can activate collagen production in hepatic stellate cells (HSCs) in a paracrine manner. Alcohol-induced hepatocyte apoptotic bodies can be phagocytosed by HSCs and Kupffer cells and result in increased expression of TGF-β1 and subsequent HSC activation. Kupffer cells may contribute to the activation of HSCs by releasing ROS and TGF- β1. Innate immunity may suppress hepatic fibrosis by killing activated HSCs and blocking TGF-β1 signaling. In patients infected with hepatitis C virus (HCV), alcohol may promote hepatic fibrosis by suppressing innate immunity. HCV core and non-structural proteins contribute to HCV-induced hepatic fibrosis. Alcohol and HCV together may promote hepatic fibrosis through increased oxidative stress and upregulation of fibrogenic cytokines. The inactive aldehyde dehydrogenase (ALDH2) and the super-active alcohol dehydrogenase (ADH2) alleles may promote hepatic fibrosis through increased accumulation of acetaldehyde in the liver. Hepatic fibrosis can be reversed by inducing selective apoptosis or necrosis of activated HSCs, or by reverse trans-differentiation of activated HSCs into the quiescent phenotype. (HEPATOLOGY 2006;43:872–878.)

Alcohol-induced liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components, especially collagen, due to increased matrix production and/or decreased matrix degradation. If alcohol consumption is continued, fibrosis may progress to cirrhosis which is a major cause of morbidity and mortality. Understanding the underlying molecular mechanisms by which chronic alcohol consumption leads to the development of liver fibrosis is important for the development of prevention and treatment of this condition. The National Institute on Alcohol Abuse and Alcoholism and Office of Rare Diseases of National Institutes of Health organized the Ron Thurman Symposium on the Mechanisms of Alcohol-Induced Hepatic Fibrosis in Santa Barbara, California, June 25, 2005, an annual symposium held in memory of one of the most innovative leaders in the field. The following topics were covered by nine speakers in the symposium: (1) Alcoholic Liver Fibrosis — Evolving Concepts and Future Directions by Scott L. Friedman; (2) Role of Acetaldehyde in Hepatic Stellate Cell Activation by Marcos Rojkind; (3) Cross Talk Between Liver Cells and Fibrogenic Response by Natalia Nieto; (4) Fat Paradox in Hepatocytes and Stellate Cells by Hidekazu Tsukamoto; (5) Signaling, HCV, and Death in Activated Hepatic Stellate Cells by David A. Brenner; (6) Alcohol, Innate Immunity and Liver Fibrosis by Bin Gao; (7) Mechanisms of Reversion of Liver Fibrosis by Derek A. Mann; (8) Genetics of Alcoholic Liver Fibrosis by Christopher P. Day; and (9) Systems Biology Approach in Liver Research by Wei Yan. The following is a summary of the symposium.

Activation of hepatic stellate cells (HSCs) is the primary event that triggers the process of fibrogenesis. Activated HSCs are the primary fibrogenic cells responsible for increased collagen production in response to liver injury.1 HSC activation is characterized by the conversion of quiescent vitamin A–storing cells into proliferative, collagen-producing, and contractile myofibroblastic cells. HSC activation can be divided into two sequential phases, initiation and perpetuation.1 The initiation phase encompasses rapid changes in gene expression and phenotype that render quiescent HSCs responsive to cytokine and other local stimuli. Initiation begins with rapid gene induction resulting from paracrine stimulation by injured hepatocytes/bile duct cells, inflammatory cells, activated macrophages, or from early changes in ECM composition. Perpetuation encompasses those cellular events that amplify the activated phenotype through enhanced growth factor expression and responsiveness. Perpetuation results from autocrine and paracrine stimulation, as well as from accelerated ECM remodeling. Upon discontinuation of the injury, HSC apoptosis represents an essential step toward reversibility of fibrosis. The summary of presentations can be divided into two parts: (A) development of fibrosis; and (B) reversion of fibrosis.

A. Development of Fibrosis

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References

The following factors contributing to the development of hepatic fibrosis were discussed in the symposium:

A1. Paracrine Effect of Hepatocytes

Alcohol is primarily metabolized in hepatocytes to acetaldehyde, a step that can be catalyzed by alcohol dehyderogenase (ADH), or cytochrome P450 2E1 (CYP2E1). Alcohol metabolism, especially through CYP2E1, leads to the release of reactive oxygen species (ROS) and generation of lipid peroxidation products.2 ROS are also generated from mitochondria during alcohol metabolism.3 Thus, alcohol metabolism leads to the generation of acetaldehyde and ROS in hepatocytes, both of which can activate HSCs through paracrine mechanism.

Role of Oxidative Stress.

Lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-nonenal (4-HNE), which may be released from alcohol-metabolizing hepatocytes, increase collagen production in cultured HSCs. Furthermore, using a co-culture of CYP2E1 transfected HepG2 cells and HSCs, it has been demonstrated ROS generated in hepatocytes can increase collagen production in HSCs.4 These results suggest hepatocytes can contribute to the activation of HSCs by generating oxidant stress.

Role of Acetaldehyde.

Acetaldehyde, an immediate metabolite of ethanol, is mostly produced in hepatocytes and can then enter HSCs in a paracrine manner. It is fibrogenic and induces the expression of both type I collagen genes in cultured HSCs by a transcriptional-dependent mechanism.5, 6 In addition, acetaldehyde upregulates transforming growth factor beta1 (TGF-β1) expression,7 suggesting some fibrogenic actions of acetaldehyde could be indirectly mediated by TGF-β1. However, more recent studies have demonstrated the early fibrogenic actions of acetaldehyde (up to ≈6 hours) are TGF-β1–independent and subsequently acetaldehyde primes HSCs to respond to the cytokine and induces TGF-β1 expression after 6 to12 hours.6

Both type I collagen genes have acetaldehyde-responsive elements that bind different transcription factors.5, 6 While the α1 (I) gene binds members of the C/EBP family of transcription factors, the α2(I) collagen gene binds Sp1 and Smad 3 and Smad 4. Acetaldehyde does not significantly change the concentrations of Smad 3 and Smad 4; however, it induces the phosphorylation of Smad 3 and the formation and activation of Smad 3-4 complexes. In contrast to TGF-β1–mediated effects, acetaldehyde has no direct effect on Smad 2 phosphorylation. These findings suggest acetaldehyde and TGF-β1 induce collagen gene expression by related but independent mechanisms. Moreover, the combined administration of acetaldehyde and TGF-β1 results in the additive upregulation of the α2(I) collagen gene.

A2. Paracrine Effect of Kupffer Cells

Kupffer cells have been implicated as mediators of alcoholic liver injury through their release of tumor necrosis factor-alpha (TNF-α), free radicals, and other inflammatory mediators in response to alcohol and lipopolysaccharide (LPS).8 TNF-α produced by activated Kupffer cells may contribute to HSC activation by inducing apoptosis of hepatocytes,9 thereby forming apoptotic bodies that have been implicated in fibrogenesis.10 In addition, Kupffer cell-derived TGF-β1 has been implicated in the activation of stellate cells through paracrine mechanism.11

The activating role of Kupffer cells has been further demonstrated using co-cultures of Kupffer cells and HSCs.12 The following features were reported in the Kupffer cell-activated HSCs: (1) phenotypic changes in HSCs as shown by stretching nuclear and cellular enlargement, cytoplasmic spreading, elongation of processes establishing contacts among cells, loss of lipid droplets and vitamin A; (2) HSC proliferation; (3) increased alpha-smooth muscle actin (α-SMA) expression; (4) increased mRNA levels of collagen I; and (5) upregulation of collagen I protein. Experiments using various antioxidants revealed that the stimulatory effect of Kupffer cells on HSC collagen I production was mediated through xanthine oxidase, NADPH oxidase, and CYP2E1, which are known source sof ROS. These results suggest a role of oxidative stress in Kupffer cell-mediated HSC activation.

A3. Role of Hepatocyte Apoptosis

Apoptosis is a form of cell death characterized by organized nuclear and ultimately cellular fragmentation. Increasing evidence suggests apoptosis of hepatocytes plays an important role in the initiation of alcoholic liver injury.13 Furthermore, hepatocyte apoptosis is significantly increased in patients with alcoholic hepatitis, and correlates with disease severity and hepatic fibrosis.14 Increased apoptosis of hepatocytes results in increased fibrosis in experimental models.15 Hepatocyte apoptosis produces chemokines and inflammation,16 which in turn may activate HSCs. Furthermore, apoptosis of hepatocytes results in generation of apoptotic bodies, which can release lipid signals for their uptake by Kupffer cells and HSCs. Phagocytosis of the apoptotic bodies by HSCs and Kupffer cells enhances their expression of pro-fibrogenic genes, such as TGF-β1, that may initiate HSC activation.17 These studies suggest alcohol-induced apoptosis of hepatocytes may be a mechanism of liver fibrosis.

A4. Role of Leptin

Leptin plays an important role in the development of hepatic fibrosis.18, 19 Leptin increases α 1 (I) collagen mRNA and type I collagen production in human stellate cell line, LX-1, and in cultured rat HSCs.19, 20 This effect of leptin can be mediated through upregulation of TGF-β1,18 enhancement of the TGF-β1 type II receptor,20 or increased production of tissue inhibitor of metalloproteinase-1 (TIMP-1)21 in activated HSCs. The role of leptin in alcoholic hepatic fibrosis is unknown.

A5. Role of Innate Immunity and Alcohol

The liver immune system has predominant innate immunity (nonspecific immunity) comprised of Kupffer cells, natural killer (NK) cells and NKT cells, and interferon alpha (IFN-α) and interferon gamma (IFN-γ) cytokines. Increasing evidence suggests these innate immune cells and cytokines play important roles in regulating the development and progression of liver fibrosis: (1) macrophages have been shown to inhibit liver fibrosis through killing HSCs and enhancing matrix degradation during recovery22; (2) innate cytokines IFN-α and IFN-γ inhibit liver fibrosis by blocking TGF-β1 signaling and HSC activation23; (3) IFN-α in combination with ribavirin has been shown to attenuate liver fibrosis in patients infected with hepatitis C virus (HCV)24; and (4) NK cells have been shown to kill activated HSCs and attenuate the severity of liver fibrosis.25 These results suggest innate immunity (NK/IFNs) plays an important role in suppression of liver fibrosis. Activation of the innate immune system (NK/IFNs) during HCV infection26 may help to control the progression of hepatic fibrosis.

Alcohol consumption–mediated suppression of the innate immunity has been reported in both animal experiments and clinical studies.27 Chronic alcohol consumption has been shown to decrease NK cell activity and numbers.28, 29 Decreased NK activity has also been reported in human alcoholics.27 Acute ethanol exposure markedly suppresses IFN-β and IFN-γ activation of STAT1 signaling pathways in primary hepatocytes.30 STAT2 and protein kinase R, which are the key downstream signaling components for IFN-α, are significantly downregulated in human alcoholic liver disease.31 Chronic alcohol consumption interferes with the efficacy of IFN-α treatment in HCV patients.32 Because these innate immune cells and cytokines play an important role in suppressing liver fibrosis as discussed previously, alcohol suppression of innate immunity may be a mechanism whereby alcohol accelerates liver fibrosis in HCV patients.

A6. HCV and Liver Fibrosis

Hepatitis C virus (HCV) is known to induce liver fibrosis but the mechanisms of this effect are not known. HCV proteins that are potentially secreted by hepatocytes induce fibrogenic effects in HSCs.33 Human activated HSCs express the mRNAs for the putative HCV receptors CD81, LDL receptor, and C1q receptor, and thus, may be infected by HCV. Incubation of activated but not quiescent human HSCs with recombinant core and NS3 proteins increased intracellular calcium concentration and ROS production, as well as stimulated intracellular signaling pathways. Adenoviruses encoding core and nonstructural proteins (NS3-NS5) were used to express HCV proteins in HSCs. Expression of core protein in human activated HSCs increased cell proliferation in a Ras/ERK and PI3K/AKT dependent manner. In contrast, NS3-NS5 protein expression predominantly induced proinflammatory actions, such as increased chemokine secretion and expression of intercellular cell adhesion molecule type 1 (ICAM-1) through the NF-kappa B and c-Jun N-terminal kinase pathways. These effects were attenuated by antioxidants. Infection of freshly isolated rat HSCs with adenovirus-encoding core protein resulted in accelerated cell activation. Moreover, adenovirus-encoding core and NS3-NS5 proteins increased the secretion of bioactive TGF-β1 and the expression of procollagen α1(I) in quiescent rat HSCs. These results suggested HCV core and nonstructural proteins regulate both distinct and overlapping biologic functions in HSCs, which are partly mediated through oxidative stress. Furthermore, HCV envelop protein E2 induces matrix metalloproteinase-2 in activated HSCs.34 Thus, a direct interaction between HCV proteins and HSCs may contribute to HCV-induced liver fibrosis.

Alcohol consumption is known to accelerate the process of liver fibrosis in patients infected with HCV, but the mechanisms of this interaction are not clear. Alcohol consumption has been shown to increase apoptosis of hepatocytes35 and oxidative stress in patients with chronic hepatitis C virus infection.36 Furthermore, HCV core protein and chronic alcohol consumption additively increased lipid peroxidation and synergistically increased hepatic TNF-α and TGF-β1 expression in HCV core protein-expressing transgenic mice.37 All these fibrogenic factors — apoptosis, oxidative stress, lipid peroxidation, TNF-α, and TGF-β1 — may be involved in promoting the effect of alcohol on hepatic fibrosis in HCV infected patients.

A7. Genetics of Fibrosis

Of those subjects who drink heavily, only about 15% to 20% will develop fibrosis/cirrhosis, suggesting only a minority of subjects are susceptible to alcohol-induced liver disease and genetic factors may contribute to this process. Although studies are not available examining polymorphism in all of the proposed fibrosis genes, some information is available on the genetic polymorphisms of those factors involved in the pathogenesis of alcoholic liver fibrosis. Some of these factors include accumulation of acetaldehyde, oxidative stress, and inflammatory cytokines.

Genetic factors that are involved in the production or elimination of acetaldehyde may make individuals susceptible to alcoholic liver disease (ALD), as acetaldehyde has been implicated in the pathogenesis of ALD. Indeed, the presence of super-active alcohol dehydrogenase (ADH2) and inactive aldehyde dehydrogenase (ALDH2) alleles has been linked to increased risk for ALD in Asian populations.38, 39 Both of these gene products will result in an excess accumulation of acetaldehyde.

Genetic factors that promote oxidative stress can make individuals susceptible to alcoholic liver injury. For example, the mutant c2 allele of CYP2E1 (that is more transcriptionally active) increases the risk of ALD at a given level of cumulative alcohol consumption.40 The risk appears to be due to increased metabolism of ethanol by CYP2E1 that produces ROS.

Genetic factors that modulate the production of pro- and anti-inflammatory cytokines can also influence the susceptibility to ALD. For example, researchers have reported an association of a TNF-α promoter polymorphism (−238 G/A) with susceptibility to alcoholic steatohepatitis.41 There was a significant excess of the rare allele (TNFA-A) at position −238 in patients with steatohepatitis compared with controls or patients without this lesion. In addition, among heavy drinkers, the presence of the A allele at position −627 in the IL-10 (an antiinflammatory cytokine) promoter is associated with an increased risk of advanced liver disease.42 This result is probably due to the fact that the −627*A allele is associated with low IL-10 expression which favors inflammation and fibrosis.

These examples suggest genetic polymorphism of alcohol metabolizing enzymes, oxidative stress, and cytokine production may contribute to the susceptibility of certain individuals to the development of alcoholic liver fibrosis.

B. Reversion of Fibrosis

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References

In theory, reversion of fibrosis may be accomplished by inducing apoptosis or necrosis of activated HSCs, or by transformation of activated HSCs to quiescent phenotype.

B1. Apoptosis of Activated HSCs

Spontaneous resolution of experimental fibrosis is associated with the clearance of collagen-producing α-SMA positive myofibroblasts (activated HSCs and transdifferentiated portal fibroblasts). This clearance has been attributed to the induction of apoptosis of these cells.43 Apoptosis of myofibroblasts is associated with decreased expression of TIMP mRNA but increased collagenase activity in the liver.43 This concept of spontaneous reversion of fibrosis mediated by HSC apoptosis has been used to design chemical-induced apoptosis of activated HSCs. For example, gliotoxin induces apoptosis of activated HSC which resulted in the resolution of liver fibrosis induced by carbon tetrachloride in experimental animals.44 In addition, sulfasalazine has been shown to induce apoptosis of activated rat and human stellate cells in vitro, and promote accelerated recovery from carbon tetrachloride-induced fibrosis in rats.45 This effect was mediated through the inhibition of the inhibitor of kappaB kinases, blocking the NFκB pathway. TIMP-1 protects activated HSCs from apoptosis,46 and blocking TIMP-1 with specific monoclonal antibody reverses CCl4-induced hepatic fibrosis.47

The key to translating the important discovery of the activated-HSC-apoptosis model of fibrosis recovery into a clinical entity of therapeutic value in diseases such as ALD is to design strategies that selectively kill activated HSCs without affecting macrophages and hepatocytes that are critical for recovery and regeneration. For example, gliotoxin is capable of inducing apoptosis not only of HSCs but also of hepatocytes at higher concentrations,48 thus limiting its clinical usefulness. On the other hand, activated HSCs selectively express the low affinity neurotrophic receptor p75 and undergo apoptosis in response to nerve growth factor stimulation.49 Thus, nerve growth factor and its related family of neurotrophic agents might be more selective for inducing HSC apoptosis. Hepatocyte growth factor (HGF) stimulates hepatocyte regeneration but apoptosis of activated HSCs and reversal of fibrosis.50

B2. Necrosis of Activated HSCs

Activated HSCs can be selectively killed by the endogenous cannabinoid anandamide via inducing necrosis.51 Anandamide blocks HSC proliferation at concentrations of 1 to 10 micromol/L. At higher concentrations (25-100 micromol/L), anandamide dose-dependently induced cell death in culture-activated and in vivo activated HSCs. The cell death was caspase independent and showed typical features of necrosis, such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide induces ROS formation and increased intracellular Ca(2+) levels. Pretreatment with the antioxidant glutathione or Ca(2+)-chelation attenuated anandamide-induced cell death. In primary hepatocytes, anandamide failed to induce cell death even after prolonged treatment. Thus, anandamide efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that anandamide may be used as a potential anti-fibrogenic tool.

B3. Reverse Transdifferentiation of Activated HSCs to Quiescent Phenotype

One theoretical approach to reverse fibrosis is the reverse transdifferentiation of activated HSCs to quiescent phenotype. Quiescent HSCs are full of vitamin A and triglycerides which are depleted in the activated HSCs. The adipogenic/lipogenic transcriptional regulation conferred by PPARγ, LXRα, and SREBP-1c is required for the maintenance of the fat-storing quiescence phenotype of HSCs. Expression of these adipogenic transcription factors is lost in activated HSCs.52 On the other hand, treatment of the activated HSCs with an adipocyte differentiation cocktail or ectopic expression of PPARγ or SREBP-1c causes their reversal to the quiescent phenotype.53, 54 Of the known adipogenic transcription factors, PPARγ has been investigated extensively. The expression of PPARγ is reduced in activated HSCs which can be restored with PPARγ ligands.52 Furthermore, by using adenoviral vector to ectopically express PPARγ in culture-activated HSCs, researchers have demonstrated expression of PPARγ can restore the morphological and biochemical characteristics of quiescent HSCs, including accumulation of vitamin A.53 This reversal was associated with decreased binding of JunD to the AP-1 site. These findings suggest a possibility that PPARγ and other adipogenic factors may serve as important therapeutic targets for liver fibrosis. Indeed, researchers have demonstrated the therapeutic efficacy of two thiazolidinedione (TZD) derivatives, the PPARγ ligands pioglitazone and rosiglitazone in two toxic and one cholestatic models of liver fibrosis.55

System Biology Approach in Liver Research

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References

Systems biology is the study of dynamic interactions and processing of molecular components within a biological system such as a cell or organism. A system biology approach was performed on the IFN response to hepatitis C-mediated liver disease (56). In this study, quantitative proteomics and microarray analyses were performed and the generated data were applied for protein interaction network visualization and modeling using Cytoscape computational platform. By integrating quantitative proteomics and microarray data with global protein interaction data, researchers were able to identify several novel and liver specific key regulatory components of IFN response, which may be important in regulating the interplay between HCV, interferon, and the host response to virus infection. This type of approach may be used in understanding the dynamic and integrated role of various factors such as cytokines, oxidative stress, inflammatory cells, apoptosis, and innate immune system in the development of hepatic fibrosis and other liver diseases.

Future Directions

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References
  • 1
    Characterization of key genes initiating HSC activation in liver fibrosis
  • 2
    Mechanisms by which quiescent HSCs lose lipid droplets and adipogenic/lipogenic factors upon activation
  • 3
    Investigation of molecular mechanisms whereby adipogenic/lipogenic regulation promotes HSC quiescence but makes hepatocytes steatotic
  • 4
    Molecular mechanisms of upregulation of collagen and TIMP production and downregulation of matrix metalloproteinases (MMPs) in alcoholic liver fibrosis
  • 5
    Understanding the role of acetaldehyde in activation, migration, and proliferation, of HSCs
  • 6
    Understanding the intracellular signaling of acetaldehyde, oxidative stress, cytokines, and ECM in initiating HSC activation in an integrative manner using system biology approach
  • 7
    Development of co-culture models of hepatocytes, Kupffer cells, and HSCs for investigating the effects of various fibrogenic mediators
  • 8
    Roles of myofibroblasts of bone marrow and portal tract origin and epithelial mesenchymal transition (if any) in alcoholic liver fibrosis
  • 9
    Elucidation of mechanisms whereby hepatocyte apoptosis triggers activation of HSCs and identification of the apoptotic signals for hepatocytes, Kupffer cells, and HSCs
  • 10
    Mechanisms of the opposite effects of TNF-α on liver fibrosis
  • 11
    Role of inflammatory cells in sustaining liver fibrosis
  • 12
    Mechanisms of interaction of innate immune system and alcohol on alcoholic liver fibrosis
  • 13
    Understanding the role of the key fibrogenic agonists leptin, adenosine, angiotensin II, and connective tissue growth factor in alcohol-induced hepatic fibrosis
  • 14
    Genome and proteome expression and whole genome single nucleotide polymorphism (SNP) scans studies in livers from a large number of patients with alcoholic liver fibrosis
  • 15
    Characterization of key genes initiating apoptosis of activated HSCs during the resolution of fibrosis
  • 16
    Identification of agents that will selectively kill activated HSCs via inducing apoptosis or necrosis
  • 17
    Understanding the role of hepatocyte growth factor/scatter factor in the resolution of hepatic fibrosis
  • 18
    Understanding of the biology of matrix resorption
  • 19
    Understanding the role of adiponectin in the regulation of hepatic fibrosis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References

We wish to thank Drs. Scott L. Friedman, Marcos Rojkind, Natalia Nieto, Hidekazu Tsukamoto, Bin Gao, Derek A. Mann, Christopher P. Day, and Wei Yan for their excellent presentations at the symposium and for providing their written summaries that were the basis of this manuscript. The National Institute on Alcohol Abuse and Alcoholism acknowledges the support provided by the Office of Rare Diseases and looks forward to continued cooperation and collaboration.

Disclaimer: The opinions expressed herein are those of authors and do not necessarily reflect the official position of NIAAA, ORD, or any other part of the National Institutes of Health.

References

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  2. Abstract
  3. A. Development of Fibrosis
  4. B. Reversion of Fibrosis
  5. System Biology Approach in Liver Research
  6. Future Directions
  7. Acknowledgements
  8. References
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